Compounds and their use as bace inhibitors

ABSTRACT

The present invention relates to compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Down&#39;s syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment”), Alzheimer&#39;s disease, memory loss, attention deficit symptoms associated with Alzheimer&#39;s disease, neurodegeneration associated with diseases such as Alzheimer&#39;s disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson&#39;s disease, progressive supranuclear palsy or cortical basal degeneration.

The present invention relates to compounds and therapeuticallyacceptable salts thereof, their pharmaceutical compositions, processesfor making them and their use as medicaments for treatment and/orprevention of various diseases. In particular the invention relates tocompounds, which are inhibitors of β-secretase and hence inhibit theformation of amyloid β (Aβ) peptides and will be used for treatmentand/or prevention of Aβ-related pathologies such as Alzheimer's disease,Down's syndrome and β-amyloid angiopathy, such as but not limited tocerebral amyloid angiopathy, hereditary cerebral hemorrhage, disordersassociated with cognitive impairment, such as but not limited to MCI(“mild cognitive impairment”), Alzheimer's disease, memory loss,attention deficit symptoms associated with Alzheimer's disease,neurodegeneration associated with diseases such as Alzheimer's diseaseor dementia including dementia of mixed vascular and degenerativeorigin, pre-senile dementia, senile dementia and dementia associatedwith Parkinson's disease, progressive supranuclear palsy or corticalbasal degeneration.

BACKGROUND

The prime neuropathological event distinguishing Alzheimer's disease(AD) is deposition of the 40-42 residue amyloid β-peptide (Aβ) in brainparenchyma and cerebral vessels. A large body of genetic, biochemicaland in vivo data support a pivotal role for Aβ in the pathologicalcascade that eventually leads to AD. Patients usually present earlysymptoms (commonly memory loss) in their sixth or seventh decades oflife. The disease progresses with increasing dementia and elevateddeposition of Aβ. In parallel, a hyperphosphorylated form of themicrotubule-associated protein tau accumulates within neurons, leadingto a plethora of deleterious effects on neuronal function. Theprevailing working hypothesis regarding the temporal relationshipbetween Aβ and tau pathologies states that Aβ deposition precedes tauaggregation in humans and animal models of the disease. Within thiscontext, it is worth noting that the exact molecular nature of Aβ,mediating this pathological function is presently an issue under intensestudy. Most likely, there is a continuum of toxic species ranging fromlower order Aβ oligomers to supramolecular assemblies such as Aβfibrils.

The Aβ peptide is an integral fragment of the Type I protein APP (Aβamyloid precursor protein), a protein ubiquitously expressed in humantissues. Since soluble Aβ can be found in both plasma and cerebrospinalfluid (CSF), and in the medium from cultured cells, APP has to undergoproteolysis. There are three main cleavages of APP that are relevant tothe pathobiology of AD, the so-called α-, β-, and γ-cleavages. Theα-cleavage, which occurs roughly in the middle of the Aβ domain in APPis executed by the metalloproteases ADAM10 or ADAM17 (the latter alsoknown as TACE). The β-cleavage, occurring at the N terminus of Aβ, isgenerated by the transmembrane aspartyl protease Beta site APP CleavingEnzyme1 (BACE1). The γ-cleavage, generating the Aβ C termini andsubsequent release of the peptide, is effected by a multi-subunitaspartyl protease named γ-secretase. ADAM10/17 cleavage followed byγ-secretase cleavage results in the release of the soluble p3 peptide,an N-terminally truncated Aβ fragment that fails to form amyloiddeposits in humans. This proteolytic route is commonly referred to asthe non-amyloidogenic pathway. Consecutive cleavages by BACE1 andγ-secretase generates the intact AP peptide, hence this processingscheme has been termed the amyloidogenic pathway. With this knowledge athand, it is possible to envision two possible avenues of lowering Aβproduction: stimulating non-amyloidogenic processing, or inhibit ormodulate amyloidogenic processing. This application focuses on thelatter strategy, inhibition or modulation of amyloidogenic processing.

Amyloidogenic plaques and vascular amyloid angiopathy also characterizethe brains of patients with Trisomy 21 (Down's Syndrome), HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), andother neurodegenerative disorders. Neurofibrillary tangles also occur inother neurodegenerative disorders including dementia-inducing disorders(Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46,4625-4630). β-amyloid deposits are predominately an aggregate of Aβpeptide, which in turn is a product of the proteolysis of amyloidprecursor protein (APP). More specifically, Aβ peptide results from thecleavage of APP at the C-terminus by one or more γ-secretases, and atthe N-terminus by β-secretase enzyme (BACE), also known as aspartylprotease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of theβ-amyloidogenic pathway.

BACE activity is correlated directly to the generation of Aβ peptidefrom APP (Sinha, et al, Nature, 1999, 402, 537-540), and studiesincreasingly indicate that the inhibition of BACE inhibits theproduction of Aβ peptide (Roberds, S. L., et al, Human MolecularGenetics, 2001, 10, 1317-1324). BACE is a membrane bound type 1 proteinthat is synthesized as a partially active proenzyme, and is abundantlyexpressed in brain tissue. It is thought to represent the majorβ-secretase activity, and is considered to be the rate-limiting step inthe production of amyloid-β-peptide (Aβ).

Drugs that reduce or block BACE activity should therefore reduce Aβlevels and levels of fragments of Aβ in the brain, or elsewhere where Aβor fragments thereof deposit, and thus slow the formation of amyloidplaques and the progression of AD or other maladies involving depositionof Aβ or fragments thereof. BACE is therefore an important candidate forthe development of drugs as a treatment and/or prophylaxis of Aβ-relatedpathologies such as Down's syndrome, β-amyloid angiopathy such as butnot limited to cerebral amyloid angiopathy or hereditary cerebralhemorrhage, disorders associated with cognitive impairment such as butnot limited to MCI (“mild cognitive impairment”), Alzheimer's Disease,memory loss, attention deficit symptoms associated with Alzheimer'sdisease, neurodegeneration associated with diseases such as Alzheimer'sdisease or dementia including dementia of mixed vascular anddegenerative origin, pre-senile dementia, senile dementia and dementiaassociated with Parkinson's disease, progressive supranuclear palsy orcortical basal degeneration. It would therefore be useful to inhibit thedeposition of Aβ and portions thereof by inhibiting BACE throughinhibitors such as the compounds provided herein.

The therapeutic potential of inhibiting the deposition of Aβ hasmotivated many groups to isolate and characterize secretase enzymes andto identify their potential inhibitors.

DISCLOSURE OF THE INVENTION

The present invention is directed to compounds according to formula (I):

wherein

A is —O— or —CH₂—;

n is 0 or 1;R¹ is C₁₋₆alkyl or C₁₋₆haloalkyl;R² is hydrogen, C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl, C₂₋₆alkynyl,C₂₋₆alkenyl, C₁₋₆alkyl, halogen, cyano, C₁₋₆haloalkyl, NHC(O)R⁹ or OR⁸,wherein said C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl, C₂₋₆alkynyl,C₂₋₆alkenyl, C₁₋₆alkyl, or C₁₋₆haloalkyl is optionally substituted withone to three R⁷;R⁵ and R⁶ are independently hydrogen, heterocyclyl, C₃₋₆cycloalkyl,aryl, heteroaryl or C₁₋₆alkyl, wherein said heterocyclyl,C₃₋₆cycloalkyl, aryl, heteroaryl or C₁₋₆alkyl is optionally substitutedwith one or two substituents independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, cyano, or OR⁸;or R⁵ and R⁶ together with the carbon to which they are attached, form aring B, which is a 3-14 membered cycloalkyl or heterocyclyl monocyclicring, or a 9-14 membered bicyclic cycloalkyl or heterocyclyl ring; andwherein ring B is optionally substituted by one or two substituentsindependently selected from oxo, halogen, C₁₋₆alkyl, C₁₋₆ haloalkyl,cyano, or OR⁸; and ring B is optionally fused with an aryl or heteroarylto form a bi- or polycyclic system;R⁷ is independently C₁₋₆alkyl, halogen, cyano, C₀₋₆alkylC₃₋₆cycloalkyl,C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, C₂₋₆alkynyl or C₂₋₆alkenyl,wherein said C₁₋₆alkyl, C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆haloalkyl,OC₁₋₆alkyl, OC₁₋₆haloalkyl, C₂₋₆alkynyl or C₂₋₆alkenyl is optionallysubstituted with 1-3 substituents independently selected from halogen,cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl, and OC₁₋₆haloalkyl;R⁸ is independently hydrogen, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,aryl or heteroaryl; wherein said C₁₋₆alkyl, C₁₋₆haloalkyl, aryl orheteroaryl is optionally substituted with a group selected from halogen,cyano, and C₁₋₆alkyl;R⁹ is a heteroaryl; wherein said heteroaryl is optionally substitutedwith halogen, cyano, OR⁸, C₁₋₆haloalkyl or C₁₋₆alkyl;as a free base or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, A is —CH₂—.

In one embodiment of the present invention, n is 0.

In one embodiment of the present invention, R¹ is C₁₋₃alkyl. In anotherembodiment of the invention, R¹ is methyl or ethyl. In yet anotherembodiment, R¹ is methyl.

In one embodiment of the present invention, R² is aryl, heteroaryl,C₂₋₆alkynyl, halogen, NHC(O)R⁹ or OR⁸, wherein said aryl, heteroaryl orC₂₋₆alkynyl is optionally substituted with one to three R⁷. In anotherembodiment of the invention, R² is aryl, heteroaryl, C₂₋₆alkynyl or OR⁸,wherein said aryl, heteroaryl or C₂₋₆alkynyl is optionally substitutedwith one to three R⁷.

In one embodiment of the present invention, R⁵ and R⁶ are independentlyhydrogen or heterocyclyl wherein said heterocyclyl is optionallysubstituted with one or two substituents independently selected fromC₁₋₆alkyl or OR⁸.

In one embodiment of the present invention, R⁵ and R⁶ together with thecarbon to which they are attached, form a ring B, which is a 3-14membered cycloalkyl or heterocyclyl monocyclic ring, or a 9-14 memberedbicyclic cycloalkyl or heterocyclyl ring; and wherein ring B isoptionally substituted by one or two substituents independently selectedfrom oxo, halogen, C₁₋₆alkyl or OR⁸; and ring B is optionally fused withan aryl or heteroaryl to form a bi- or polycyclic system.

In another embodiment of the invention, R⁵ and R⁶ together with thecarbon to which they are attached, form a ring B, which is a 3-14membered cycloalkyl monocyclic ring; and wherein ring B is optionallysubstituted by one or two substituents independently selected from oxo,halogen, C₁₋₆alkyl or OR⁸. In yet another embodiment, R⁵ and R⁶ togetherwith the carbon to which they are attached form a cyclohexyl ring, whichis substituted with OR⁸.

In one embodiment of the present invention, R⁷ is independentlyC₁₋₆alkyl, halogen, cyano, C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆haloalkyl,OC₁₋₆alkyl or C₂₋₆alkynyl, wherein said C₁₋₆alkyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl, or C₂₋₆alkynyl isoptionally substituted with 1-3 substituents independently selected fromhalogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl and OC₁₋₆haloalkyl.In another embodiment of the invention, R⁷ is halogen, cyano,C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl or C₂₋₆alkynyl,wherein said C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl, orC₂₋₆alkynyl is optionally substituted with 1-3 substituentsindependently selected from OC₁₋₆alkyl and OC₁₋₆haloalkyl.

In one embodiment of the present invention, R⁸ is independentlyC₁₋₆alkyl, C₂₋₆alkynyl or C₁₋₆haloalkyl. In another embodiment of theinvention, R⁸ is independently C₁₋₆alkyl or C₁₋₆haloalkyl.

In one embodiment of the present invention, R⁹ is heteroaryl; whereinsaid heteroaryl is optionally substituted with halogen, cyano, OR⁸,C₁₋₆haloalkyl or C₁₋₆alkyl.

In one embodiment of the present invention,

A is —O— or —CH₂—;

n is 0 or 1;R¹ is C₁₋₆alkyl;R² is C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl, C₂₋₆alkynyl, halogen, NHC(O)R⁹or OR⁸; wherein said C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl or C₂₋₆alkynylis optionally substituted with one to three R⁷;R⁵ and R⁶ are independently hydrogen or heterocyclyl, wherein saidheterocyclyl, is optionally substituted with one or two substituentsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, cyano orOR⁸;or R⁵ and R⁶ together with the carbon to which they are attached, form aring B, which is a 3-14 membered cycloalkyl or heterocyclyl monocyclicring, or a 9-14 membered bicyclic cycloalkyl or heterocyclyl ring; andwherein ring B is optionally substituted by one or two substituentsindependently selected from oxo, halogen, C₁₋₆alkyl or OR⁸; and ring Bis optionally fused with an aryl or heteroaryl to form a bi- orpolycyclic system;R⁷ is independently C₁₋₆alkyl, halogen, cyano, C₀₋₆alkylC₃₋₆cycloalkyl,C₁₋₆ haloalkyl, OC₁₋₆alkyl or C₂₋₆alkynyl, wherein said C₁₋₆alkyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl or C₂₋₆alkynyl isoptionally substituted with 1-3 substituents independently selected fromhalogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl and OC₁₋₆haloalkyl;R⁸ is independently C₁₋₆alkyl, C₂₋₆alkynyl or C₁₋₆haloalkyl; whereinsaid C₁₋₆alkyl, C₁₋₆haloalkyl, aryl or heteroaryl is optionallysubstituted with a group selected from halogen, cyano, or C₁₋₆alkyl;R⁹ is heteroaryl, wherein said heteroaryl is optionally substituted withhalogen, cyano, OR⁸, C₁₋₆haloalkyl or C₁₋₆alkyl.

In one embodiment of the present invention,

A is —O— or —CH₂—;

n is 0 or 1;R¹ is C₁₋₆alkyl;R² is aryl, heteroaryl, C₂₋₆alkynyl, halogen, NHC(O)R⁹ or OR⁸, whereinsaid aryl, heteroaryl or C₂₋₆alkynyl is optionally substituted with oneto three R⁷;R⁵ and R⁶ are independently hydrogen or heterocyclyl, wherein saidheterocyclyl is optionally substituted with two substituentsindependently selected from C₁₋₆alkyl;or R⁵ and R⁶ together with the carbon to which they are attached, form aring B, which is a 3-14 membered cycloalkyl or heterocyclyl monocyclicring, or a 9-14 membered bicyclic cycloalkyl or heterocyclyl ring; andwherein ring B is optionally substituted by one or two substituentsindependently selected from oxo, halogen, C₁₋₆alkyl or OR⁸; and ring Bis optionally fused with an aryl or heteroaryl to form a bicyclicsystem;R⁷ is independently C₁₋₆alkyl, halogen, cyano, C₀₋₆alkylC₃₋₆cycloalkyl,C₁₋₆haloalkyl, OC₁₋₆alkyl or C₂₋₆alkynyl, wherein said C₁₋₆alkyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl or C₂₋₆alkynyl, isoptionally substituted with 1-3 substituents independently selected fromhalogen, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl and OC₁₋₆haloalkyl;R⁸ is independently C₁₋₆alkyl, C₂₋₆alkynyl or C₁₋₆haloalkyl; whereinsaid C₁₋₆alkyl, C₁₋₆haloalkyl, aryl or heteroaryl is optionallysubstituted with a group selected from halogen, cyano or C₁₋₆alkyl; andR⁹ is heteroaryl, wherein said heteroaryl is optionally substituted withhalogen, cyano, OR⁸, C₁₋₆haloalkyl or C₁₋₆alkyl.

In one embodiment of the present invention,

A is —CH₂—;

n is 0;R¹ is methyl or ethyl;R² is aryl, heteroaryl or C₂₋₆alkynyl, wherein said aryl, heteroaryl orC₂₋₆alkynyl is optionally substituted with one to three R⁷;R⁵ and R⁶ together with the carbon to which they are attached form acyclohexyl ring, which is substituted with OR⁸;R⁷ is independently C₁₋₃alkyl, halogen, cyano or C₂₋₆alkynyl;R⁸ is C₁₋₃alkyl.

In one embodiment of the present invention,

A is —CH₂—;

n is 0;R¹ is methyl or ethyl;R² is phenyl or pyridinyl, wherein said phenyl or pyridinyl isoptionally substituted with one or two R⁷;R⁵ and R⁶ together with the carbon to which they are attached form acyclohexyl ring, which is substituted with methoxy;R⁷ is independently Chloro, fluoro, cyano or prop-1-yn-1-yl.

In one embodiment, the compound of formula (I) has the followingconfiguration:

In another embodiment, the invention relates to a compound of formula(I) selected from the group consisting of:

-   6-(3,5-dichlorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(5-chloropyridin-3-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(3,5-difluorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(3,5-dimethylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(2,5-dimethoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(2,3-difluorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(2,5-dimethylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(5-fluoro-2-methoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(2-fluoro-3-methoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(2-methoxy-5-methylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(2-fluoro-5-methylphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   6-(2-fluoro-5-methoxyphenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine;-   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-chloro-pyridine-2-carboxamide;-   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-(trifluoromethyl)pyridine-2-carboxamide;-   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-but-2-ynoxy-pyridine-2-carboxamide;-   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-but-2-ynoxy-pyrazine-2-carboxamide;-   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-5-methyl-thiophene-2-carboxamide;-   N-(4′-amino-5′-methyl-spiro[chromane-4,2′-imidazole]-6-yl)-3,5-dichloro-pyridine-2-carboxamide;-   6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-[4-(prop-1-yn-1-yl)pyridin-2-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)benzene-1,3-dicarbonitrile;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;-   6′-(5-chloropyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-fluoropyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluorobenzonitrile;-   6′-(3,3-dimethylbut-1-yn-1-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(cyclopropylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-bromopyrimidine-2-carboxamide;-   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(trifluoromethyl)pyridine-2-carboxamide;-   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloro-3-methyl-1-benzofuran-2-carboxamide;-   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-3,5-dichloropyridine-2-carboxamide;-   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloropyridine-2-carboxamide;-   4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(3-fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,    1′-indene-2′,4″-pyran]-4-amine;-   6′-(3-chlorophenyl)-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine;-   6′-(3-chloro-4-fluorophenyl)-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine;-   6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-chloropyridin-3-yl)-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   N-(4″-amino-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloropyridine-2-carboxamide;-   5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;-   5′-(3-chlorophenyl)-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;-   6′-bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine;-   6′-(3-chlorophenyl)-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine;-   6′-(3-chloro-4-fluorophenyl)-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine;-   6-bromo-5′-methyl-2-tetrahydropyran-3-yl-spiro[chromane-4,2′-imidazole]-4′-amine;-   6-(3-chlorophenyl)-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2,3-dihydrospiro[chromene-4,2′-imidazol]-4′-amine;-   6-bromo-2-(2,2-dimethyltetrahydropyran-4-yl)-5′-methyl-spiro[chromane-4,2′-imidazole]-4′-amine;-   6-(3-chlorophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methyl-2,3-dihydrospiro[chromene-4,2′-imidazol]-4′-amine;-   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloro-3-methylpyridine-2-carboxamide;-   N-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluoropyridine-2-carboxamide;-   4-methoxy-5″-methyl-6′-[2-(prop-1-yn-1-yl)pyridin-4-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine-   4-methoxy-5″-methyl-6′-[3-(prop-1-yn-1-yl)phenyl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-bromopyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4,4-difluoro-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5′-(5-chloropyridin-3-yl)-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-5′-[5-(prop-1-yn-1-yl)pyridin-3-yl]dispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine;-   7′-bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine;-   7′-(5-chloropyridin-3-yl)-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine;-   5-methyl-7′-(5-(prop-1-ynyl)pyridin-3-yl)-3′,4′-dihydro-2′H-spiro[imidazole-2,    1′-naphthalen]-4-amine;-   6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-chloropyridin-3-yl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(cyclopropylethynyl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(3,    3-dimethylbut-1-yn-1-yl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-chloro-6-methylpyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-chloro-2-methylpyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-[4-methyl-5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-chloropyridin-3-yl)-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5″-ethyl-4-methoxy-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5-(4″-amino-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)pyridine-3-carbonitrile;-   3-(4″-amino-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)benzonitrile;-   6′-[5-(but-1-yn-1-yl)pyridin-3-yl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4″-amino-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-methylbenzonitrile;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;-   6′-bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;-   4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-6′-carbonitrile;-   4-methoxy-6′-[3-(methoxymethyl)phenyl]-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-[3-fluoro-5-(methoxymethyl)phenyl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-{5-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-(5-methylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(trifluoromethyl)benzonitrile;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(difluoromethyl)benzonitrile;-   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluoro-3-methoxybenzonitrile;-   6′-(3,5-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(2-fluoro-3-methoxyphenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-phenyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-methoxybenzonitrile;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-bromobenzonitrile;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-ethylbenzonitrile;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(methoxymethyl)benzonitrile;-   6′-(2-fluoro-5-methoxyphenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(2,5-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-3-chloro-2-fluorobenzonitrile;-   6′-(2,3-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-4-fluorobenzonitrile;-   6′-(2,4-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(2,3-dichlorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;-   3-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-methoxybenzonitrile;-   4-(difluoromethoxy)-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;-   4-(difluoromethoxy)-6′-(3,5-difluorophenyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5-(4″-amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluoro-3-methoxybenzonitrile;-   4-methoxy-4,5″-dimethyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(cyclobutylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-(3-methylbut-1-yn-1-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-{5-[(²H₃)prop-1-yn-1-yl]pyridin-3-yl}-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-5″-methyl-4-oxodispiro[cyclohexane-1,2′-[1H]indene-1′(3′N),2″-[2H]imidazol]-6′-yl)-5-fluorobenzonitrile;-   4-methoxy-5″-methyl-6′-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-5″-methyl-4-[(²H₁)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;-   6′-(5-chloropyridin-3-yl)-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-[5-(difluoromethyl)pyridin-3-yl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   4-methoxy-5″-methyl-6′-(3-methyl-1H-indol-5-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5″-methyl-4-[(²H₃)methyloxy]-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-[2-chloro-3-(prop-1-yn-1-yl)phenyl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;-   6′-(cyclobutylmethoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   5-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-2-fluoro-3-(methoxymethyl)benzonitrile;-   6′-bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-(5-chloropyridin-3-yl)-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   6′-bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;    4-ethoxy-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-fluorobenzonitrile;-   6′-(5-chloropyridin-3-yl)-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-(difluoromethyl)benzonitrile;    and-   4-ethoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine,    or a pharmaceutically acceptable salt of any foregoing compound.

In another embodiment, the invention relates to a compound of formula(I) selected from the group consisting of:

-   4-methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile;    and-   4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine,    or a pharmaceutically acceptable salt of any foregoing compound.

In another embodiment, the invention relates to a compound of formula(I) selected from the group consisting of:

-   (1r,4r)-4-methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-[(1r,4r)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile;    and-   (1r,4r)-4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine,    or a pharmaceutically acceptable salt of any foregoing compound.

In another embodiment, the invention relates to a compound of formula(I) selected from the group consisting of:

-   (1r,1′R,4R)-4-methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine;-   3-[(1r,1′R,4R)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile;    and-   (1r,4r)-4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine    (isomer 1);    or a pharmaceutically acceptable salt of any foregoing compound.

In yet another embodiment, the invention relates to a compound offormula (I), or a pharmaceutically acceptable salt thereof, with theproviso that any of the specific Examples are individually disclaimed.

Thus, in a further embodiment the invention relates to a compound offormula (I), or a pharmaceutically acceptable salt thereof, with theproviso that the compound is not4-methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine.

In yet a further embodiment the invention relates to a compound offormula (I), or a pharmaceutically acceptable salt thereof, with theproviso that the compound is not3-(4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile.

In yet a further embodiment the invention relates to a compound offormula (I), or a pharmaceutically acceptable salt thereof, with theproviso that the compound is not4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine.

The present invention relates to the use of compounds of formula (I) ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula (I).

The compounds of the formula (I) may be administered in the form of aprodrug which is broken down in the human or animal body to give acompound of the formula (I). Examples of prodrugs include in vivohydrolysable esters of a compound of the formula (I). An in vivohydrolysable (or cleavable) ester of a compound of the formula (I) thatcontains a carboxy or a hydroxy group is, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Various forms ofprodrugs are known in the art.

The definitions set forth in this application are intended to clarifyterms used throughout this application. The term “herein” means theentire application.

A variety of compounds in the present invention may exist in particulargeometric or stereoisomeric forms. The present invention takes intoaccount all such compounds, including tautomers, cis- and trans isomers,R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, theracemic mixtures thereof, and other mixtures thereof, as being coveredwithin the scope of this invention. Additional asymmetric carbon atomsmay be present in a substituent such as an alkyl group. All suchisomers, as well as mixtures thereof, are intended to be included inthis invention. The compounds herein described may have asymmetriccenters. Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms, by synthesis from optically activestarting materials, or synthesis using optically active reagents. Whenrequired, separation of the racemic material can be achieved by methodsknown in the art. Many geometric isomers of olefins, C═N double bonds,and the like can also be present in the compounds described herein, andall such stable isomers are contemplated in the present invention. Cisand trans geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms. All chiral, diastereomeric, racemic forms andall geometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents, positions of substituentsand/or variables are permissible only if such combinations result instable compounds.

As used in this application, the term “optionally substituted” meansthat substitution is optional and therefore it is possible for thedesignated atom or moiety to be unsubstituted.

As used herein, “alkyl”, used alone or as a suffix or prefix, isintended to include both branched and straight chain saturated aliphatichydrocarbon groups having from 1 to 12 carbon atoms or if a specifiednumber of carbon atoms is provided then that specific number would beintended. For example “C₀₋₆alkyl” denotes alkyl having 0, 1, 2, 3, 4, 5or 6 carbon atoms. Examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl,pentyl, and hexyl. In the case where a subscript is the integer 0 (zero)the group to which the subscript refers to indicates that the group maybe absent, i.e. there is a direct bond between the groups.

As used herein, “alkenyl” used alone or as a suffix or prefix isintended to include both branched and straight-chain alkene or olefincontaining aliphatic hydrocarbon groups having from 2 to 12 carbon atomsor if a specified number of carbon atoms is provided then that specificnumber would be intended. For example “C₂₋₆alkenyl” denotes alkenylhaving 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl include, butare not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl,3-pentenyl and 4-hexenyl.

As used herein, “alkynyl” used alone or as a suffix or prefix isintended to include to include both branched and straight-chain alkynylor olefin containing aliphatic hydrocarbon groups having from 2 to 12carbon atoms or if a specified number of carbon atoms is provided thenthat specific number would be intended. For example ethynyl, propynyl(e.g. 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and1-methylpent-2-ynyl.

As used herein, “aromatic” refers to hydrocarbonyl groups having one ormore unsaturated carbon ring(s) having aromatic characters, (e.g. 4n+2delocalized electrons) and comprising up to 14 carbon atoms. In addition“heteroaromatic” refers to groups having one or more unsaturated ringscontaining carbon and one or more heteroatoms such as nitrogen, oxygenor sulphur having aromatic character (e.g. 4n+2 delocalized electrons).

As used herein, the term “aryl” refers to an aromatic ring structuremade up of from 5 to 14 carbon atoms. Ring structures containing 5, 6, 7and 8 carbon atoms would be single-ring aromatic groups, for example,phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, or 14 would bepolycyclic, for example naphthyl. The aromatic ring can be substitutedat one or more ring positions with such substituents as described above.The term “aryl” also includes polycyclic ring systems having two or morecyclic rings in which two or more carbons are common to two adjoiningrings (the rings are “fused rings”) wherein at least one of the rings isaromatic, for example, the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. Examples ofpolycyclic rings include, but are not limited to,2,3-dihydro-1,4-benzodioxine and 2,3-dihydro-1-benzofuran.

As used herein, the terms “cycloalkyl” or “carbocyclyl” are intended toinclude saturated ring groups, having the specified number of carbonatoms. These may include fused or bridged polycyclic systems.Cycloalkyls have from 3 to 14 carbon atoms in their ring structure. Inone embodiment, cycloalkyls have 3, 4, 5, or 6 carbons in the ringstructure. For example, “C₃₋₆cycloalkyl” denotes such groups ascyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkenyl” is intended to includeunsaturated ring groups, having the specified number of carbon atoms.These may include fused or bridged polycyclic systems. Cycloalkenyls mayhave from 3 to 10 carbon atoms in their ring structure. In oneembodiment, cycloalkenyls have 3, 4, 5, or 6 carbons in the ringstructure. For example, “C₃₋₆cycloalkenyl” denotes such groups ascyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo.

“Counterion” is used to represent a small, negatively or positivelycharged species such as chloride, bromide, hydroxide, acetate, sulfate,tosylate, benezensulfonate, ammonium, lithium ion and sodium ion and thelike.

As used herein, the term “heterocyclyl” or “heterocyclic” or“heterocycle” refers to a saturated, unsaturated or partially saturated,monocyclic, bicyclic or tricyclic ring (unless otherwise stated)containing 3 to 20 atoms of which 1, 2, 3, 4 or 5 ring atoms are chosenfrom nitrogen, sulphur or oxygen, which may, unless otherwise specified,be carbon or nitrogen linked, wherein a —CH₂— group is optionally bereplaced by a —C(O)—; and where unless stated to the contrary a ringnitrogen or sulphur atom is optionally oxidised to form the N-oxide orS-oxide(s) or a ring nitrogen is optionally quarternized; wherein a ringNH is optionally substituted with acetyl, formyl, methyl or mesyl; and aring is optionally substituted with one or more halo. It is understoodthat when the total number of S and O atoms in the heterocyclyl exceeds1, then these heteroatoms are not adjacent to one another. If the saidheterocyclyl group is bi- or tricyclic then at least one of the ringsmay optionally be a heteroaromatic or aromatic ring provided that atleast one of the rings is non-heteroaromatic. If the said heterocyclylgroup is monocyclic then it must not be aromatic. Examples ofheterocyclyls include, but are not limited to, piperidinyl,N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl,N-mesylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl,morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl,tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl,tetrahydro-thiopyranyl, tetrahydro-thiopyran 1-oxide,tetrahydro-thiopyran 1,1-dioxide, 1H-pyridin-2-one, and2,5-dioxoimidazolidinyl.

As used herein, “heteroaryl” refers to a heteroaromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groupsinclude without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, furyl (i.e. furanyl), quinolyl,isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, benzoxazolyl,aza-benzoxazolyl imidazothiazolyl, benzo[1,4]dioxinyl,benzo[1,3]dioxolyl and the like. In some embodiments, the heteroarylgroup has from 1 to 20 carbon atoms, and in further embodiments from 3to 20 carbon atoms. In some embodiments, the heteroaryl group contains 3to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In someembodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.

As used herein, “haloalkyl”, used alone or as a suffix or prefix, isintended to include both branched and straight chain saturated aliphatichydrocarbon groups, having at least one halogen substituent and havingfrom 1 to 12 carbon atoms or if a specified number of carbon atoms isprovided then that specific number would be intended. For example“C₀₋₆haloalkyl” denotes alkyl having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.Examples of haloalkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, chlorofluoromethyl, 1-fluoroethyl,3-fluoropropyl, 2-chloropropyl, 3,4-difluorobutyl.

As used herein, the phrase “protecting group” means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 3^(rd) ed.; Wiley: New York,1999).

As used herein, “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, such non-toxicsalts include those derived from inorganic acids such as hydrochloricacid.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like diethyl ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

The present invention further includes all tautomeric forms of compoundsof the invention. As used herein, “tautomer” means other structuralisomers that exist in equilibrium resulting from the migration of ahydrogen atom. For example, keto-enol tautomerism where the resultingcompound has the properties of both a ketone and an unsaturated alcohol.Other examples of tautomerism include 2H-imidazole-4-amine and itstautomer 1,2-dihydroimidazol-5-imine, and 2H-imidazol-4-thiol and itstautomer 1,2-dihydroimidazol-5-thione. It is understood that in compoundrepresentations throughout this description, only one of the possibletautomers of the compound is drawn or named.

As used herein “stable compound” and “stable structure” are meant toindicate a compound that is sufficiently robust to survive isolation toa useful degree of purity from a reaction mixture, and formulation intoan efficacious therapeutic agent.

Compounds of the invention further include hydrates and solvates.

The present invention further includes isotopically-labelled compoundsof the invention. An “isotopically” or “radio-labelled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable isotopes that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labelled compounds will depend on thespecific application of that radio-labelled compound. For example, forin vitro receptor labelling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labelled compound” is a compound that hasincorporated at least one radionuclide. In some embodiments theradionuclide is selected from the group consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵Sand ⁸²Br.

Compounds of the present invention may be administered orally,parenteral, buccal, vaginal, rectal, inhalation, insufflation,sublingually, intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracically, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

The quantity of the compound to be administered will vary for thepatient being treated and will vary from about 100 ng/kg of body weightto 100 mg/kg of body weight per day. For instance, dosages can bereadily ascertained by those skilled in the art from this disclosure andthe knowledge in the art. Thus, the skilled artisan can readilydetermine the amount of compound and optional additives, vehicles,and/or carrier in compositions and to be administered in methods of theinvention.

In another aspect, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, for use as a medicament,e.g. for treatment or prevention of Aβ-related pathologies.

In another aspect, the invention relates to the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for treatment or prevention of Aβ-relatedpathologies.

In another aspect, the invention relates to a method of treating orpreventing Aβ-related pathologies in a mammal, such as a human being,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

The compounds of the invention, and their pharmaceutically acceptablesalts, thereby provide methods of treatment of Aβ-related pathologies,such as, but not limited to, Alzheimer's disease, Down's syndrome,β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebralhemorrhage, a disorder associated with cognitive impairment, MCI (“mildcognitive impairment”), memory loss, attention deficit symptomsassociated with Alzheimer's disease, neurodegeneration associated withAlzheimer's disease, dementia of mixed vascular origin, dementia ofdegenerative origin, pre-senile dementia, senile dementia, dementiaassociated with Parkinson's disease, progressive supranuclear palsytraumatic brain injury and cortical basal degeneration.

In another aspect, the invention relates to a pharmaceutical compositioncomprising as active ingredient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof,in association with at least one pharmaceutically acceptable excipient,carrier or diluent.

In another aspect, the invention relates to a method of inhibitingactivity of BACE with a compound according to formula (I).

In another aspect, the invention relates to a method of treating orpreventing an Aβ-related pathology in a mammal, such as a human being,comprising administering to said patient a therapeutically effectiveamount of a compound according to formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one cognitive enhancing agent,memory enhancing agent, or choline esterase inhibitor, wherein saidAβ-related pathology is Alzheimer's disease.

In another aspect, the invention relates to a pharmaceutical compositioncomprising (i) a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, (ii) an additional therapeutic agent, or apharmaceutically acceptable salt thereof, and (iii) pharmaceuticallyacceptable excipients, carriers or diluents.

In another aspect, the invention relates to a pharmaceutical compositioncomprising (i) a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, (ii) at least one agent selected from the groupconsisting of cognitive enhancing agents, memory enhancing agents andcholine esterase inhibitors, and (iii) pharmaceutically acceptableexcipients, carriers or diluents.

The treatment of Aβ-related pathology defined herein may be applied as amono therapy or may involve, in addition to the compound of theinvention, conjoint treatment with conventional therapy of value intreating one or more disease conditions referred to herein. Suchconventional therapy may include one or more of the following categoriesof agents: acetyl cholinesterase inhibitors, anti-inflammatory agents,cognitive and/or memory enhancing agents or atypical antipsychoticagents. Cognitive enhancing agents, memory enhancing agents and acetylcholine esterase inhibitors includes, but not limited to, donepezil(ARICEPT), galantamine (REMTNYL or RAZADYNE), rivastigmine (EXELON),tacrine (COGNEX) and memantine (NAMENDA, AXURA or EBIXA). Atypicalantipsychotic agents includes, but not limited to, olanzapine (marketedas ZYPREXA), aripiprazole (marketed as ABILIFY), risperidone (marketedas RISPERDAL), quetiapine (marketed as SEROQUEL), clozapine (marketed asCLOZARIL), ziprasidone (marketed as GEODON) and olanzapine/fluoxetine(marketed as SYMBYAX).

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of theinvention.

Additional conventional therapy may include one or more of the followingcategories of agents:

(i) antidepressants such as agomelatine, amitriptyline, amoxapine,bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine,elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine,ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine,phenelzine, protriptyline, ramelteon, reboxetine, robalzotan,sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone,trimipramine, venlafaxine and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof.(ii) atypical antipsychotics including for example quetiapine andpharmaceutically active isomer(s) and metabolite(s) thereof.(iii) antipsychotics including for example amisulpride, aripiprazole,asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine,chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone,haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine,olanzapine, paliperidone, perlapine, perphenazine, phenothiazine,phenylbutylpiperidine, pimozide, prochlorperazine, risperidone,sertindole, sulpiride, suproclone, suriclone, thioridazine,trifluoperazine, trimetozine, valproate, valproic acid, zopiclone,zotepine, ziprasidone and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof.(iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam,bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate,chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam,fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam,meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam,reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam,zolazepam and equivalents and pharmaceutically active isomer(s) andmetabolite(s) thereof.(v) anticonvulsants including for example carbamazepine, clonazepam,ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide,lamotrogine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin,pregabaline, rufinamide, topiramate, valproate, vigabatrine, zonisamideand equivalents and pharmaceutically active isomer(s) and metabolite(s)thereof.(vi) Alzheimer's therapies including for example donepezil,rivastigmine, galantamine, memantine, and equivalents andpharmaceutically active isomer(s) and metabolite(s) thereof.(vii) Parkinson's therapies including for example deprenyl, L-dopa,Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comPinhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors,NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors ofneuronal nitric oxide synthase and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof.(viii) migraine therapies including for example almotriptan, amantadine,bromocriptine, butalbital, cabergoline, dichloralphenazone,dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan,pergolide, pizotiphen, pramipexole, rizatriptan, ropinirole,sumatriptan, zolmitriptan, zomitriptan, and equivalents andpharmaceutically active isomer(s) and metabolite(s) thereof.(ix) stroke therapies including for example thrombolytic therapy with egactivase and desmoteplase, abciximab, citicoline, clopidogrel,eptifibatide, minocycline, and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof.(x) urinary incontinence therapies including for example darafenacin,falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodineand equivalents and pharmaceutically active isomer(s) and metabolite(s)thereof.(xi) neuropathic pain therapies including for example lidocain,capsaicin, and anticonvulsants such as gabapentin, pregabalin, andantidepressants such as duloxetine, venlafaxine, amitriptyline,klomipramine, and equivalents and pharmaceutically active isomer(s) andmetabolite(s) thereof.(xii) nociceptive pain therapies such as paracetamol, NSAIDS and coxibs,such as celecoxib, ctoricoxib, lumiracoxib, valdecoxib, parccoxib,diclofenac, loxoprofen, naproxen, ketoprofen, ibuprofen, nabumeton,meloxicam, piroxicam and opioids such as morphine, oxycodone,buprenorfin, tramadol, and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof.(xiii) insomnia therapies including for example agomelatine,allobarbital, alonimid, amobarbital, benzoctamine, butabarbital,capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol,etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone,melatonin, mephobarbital, methaqualone, midaflur, nisobamate,pentobarbital, phenobarbital, propofol, ramelteon, roletamide,triclofos, sccobarbital, zaleplon, zolpidem and equivalents andpharmaceutically active isomer(s) and metabolite(s) thereof.(xiv) mood stabilizers including for example carbamazepine, divalproex,gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate,valproic acid, verapamil, and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof.

Such combination products employ the compounds of this invention withinthe dosage range described herein and the other pharmaceutically activecompound or compounds within approved dosage ranges and/or the dosagedescribed in the publication reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows Example 20d Isomer 1 bound to the BACE active site at 1.8Å resolution. 2Fo-Fc map contoured at 1.7 sigma.

FIG. 1B shows Example 20d Isomer 1 bound to the BACE active site at 1.8Å resolution. 2Fo-Fc map contoured at 1.7 sigma.

FIG. 2A shows Example 48 Isomer 1 bound to the BACE active site at 1.40Å resolution. 2Fo-Fc map contoured at 1.3 sigma.

FIG. 2B shows Example 48 Isomer 1 bound to the BACE active site at 1.40Å resolution. 2Fo-Fc map contoured at 1.3 sigma.

FIG. 3A shows Example 48 Isomer 8 bound to the BACE active site at 1.45Å resolution. 2Fo-Fc map contoured at 1.1 sigma.

FIG. 3B shows Example 48 Isomer 8 bound to the BACE active site at 1.45Å resolution. 2Fo-Fc map contoured at 1.1 sigma.

FIG. 4A shows Example 48 Isomer 7 bound to the BACE active site at 1.35Å resolution. 2Fo-Fc map contoured at 1.3 sigma.

FIG. 4B shows Example 48 Isomer 7 bound to the BACE active site at 1.35Å resolution. 2Fo-Fc map contoured at 1.3 sigma.

PREPARATION OF COMPOUNDS

The compounds of the present invention can be prepared as a free base ora pharmaceutically acceptable salt thereof by the processes describedbelow. Throughout the following description of such processes it isunderstood that, where appropriate, suitable protecting groups will beadded to, and subsequently removed from the various reactants andintermediates in a manner that will be readily understood by one skilledin the art of organic synthesis. Conventional procedures for using suchprotecting groups as well as examples of suitable protecting groups arefor example described in Protective Groups in Organic Synthesis by T. W.Greene, P. G. M Wutz, 3^(rd) Edition, Wiley-Interscience, New York,1999. It is understood that microwaves (MW) can alternatively be usedfor the heating of reaction mixtures. Another aspect of the presentinvention provides a process for preparing a compound of formula (I), ora pharmaceutically acceptable salt thereof, wherein, unless specifiedotherwise, R¹-R⁹, n and A are defined as for formula (I) above, or aregroups that can be converted into R¹-R⁹, or A in subsequenttransformations. A compound of formula (XI) may be equivalent to acompound of formula (I). LG represents a leaving group such as halogen(such as chlorine, bromine or iodine) or an alkyl-, aryl- orhaloalkyl-sulfonate (such as triflate) and PG represents a protectinggroup. Said process comprises of:

Method (i): Formation of a Corresponding Compound of Formula (IIIa):

A ketone of formula (II), is treated with a suitable base such as sodiumhydride, KOtBu, or LDA in presence of a (his-substituted) alkyl halide,triflate or mesylate to give a compound of formula (IIIa) (Scheme 1).Said reaction may be performed at a temperature range between −78° C.and +50° C., in a suitable solvent, such as tetrahydrofuran ordimethylformamide. Alkylations could be carried out in a sequential waywith intermediates isolated and purified or in a one-pot stepwisefashion. If the reactions yield a product substituted with a olefin,cyano, sulfone or the like it could optionally be reacted further byDieckman cyclization, RCM, nucleophilic substitution or cycloaddition togive highly substituted spirocyclic intermediates.

Method (ii): Formation of a Corresponding Compound of Formula (IIIa):

A ketone of formula (II), is reacted with an aldehyde or ketone such asformaldehyde in a temperature range between room temperature and +100°C. in presence of any protic acid such as a boronic acid (such asPhB(OH)₂), or in the presence of N-Methylanilinium trifluoroacetate, ina suitable solvent such as benzene or toluene (Scheme 2). Theintermediate (IV), wherein Z and Y are defined as for example hydrogenor alkyl, can be reacted with various dienes utilizing the Diels-Alderreaction in a temperature range between room temperature and +220° C.optionally in a sealed tube. The reaction can be carried out neat or ina suitable solvent such as benzene, toluene or THF. A Lewis acid or anyother agents that may assist the reaction can be added to yield enrichedenantiomers or diastereomers. The resulting spirocyclic ring mayoptionally contain one or more substituent which may be furtherconverted by known functional group transformations.

Method (iii): Formation of a Corresponding Compound of Formula (IIIa):

An alkyl or cycloalkyl or heterocycloalkyl derivative (V) containingelectron withdrawing groups X such as cyano, carboxylic acid oralkylesters can be alkylated with optionally substituted ortho-halobenzyl bromides or chlorides (VI) (Y=halogen such as bromo or chloro)(Scheme 3). Said reaction is assisted by a base such as LDA, NaH orLiHMDS in a solvent such as benzene, THF or toluene at temperature rangebetween −78° C. and 80° C. An alkylated intermediate (VII) can beisolated and further subjected to a base such as BuLi or LDA in solventssuch as THF to effect ring cyclizations. Alternatively one can alsoutilize transition metal chemistry such as Pd, Cu or Rh containingchelating agents such as phosphine derivatives or amines in solventssuch as DMF, THF or toluene in presence of a base such as triethylamineor sodium carbonate at temperature range between room temperature and+100° C. In the event where the product (VII) from the reaction containsa substituent such as olefin, sulfone, cyano, and the like, they can befurther manipulated (Scheme 3) by RCM, cycloaddition, nucleophilicsubstitution or any other known reaction to give highly substitutedspirocyclic compounds (IIIa).

Method (iv) Formation of a Corresponding Compound of Formula (XIa):

A ketone of formula (ITT), is reacted with ammonia to form intermediate(VIII) (Scheme 4). The compound of formula (VIII) is optionally notisolated and may be submitted to the next step immediately in a one potsystem. Compound (VIII) is further reacted with ethyl 2-oxopropanoate toform an imidazole compound of formula (IX). Said reaction may beperformed at a temperature range between room temperature and +160° C.,in a suitable solvent, such as methanol, ethanol or isopropyl alcohol.

The amino imidazole compound (XIa) may then be obtained by formation ofintermediate (Xa), by reacting the alcohol of formula (IX), with asulphurating reagent such as phosphorus pentasulfide in the presence ofa base such as pyridine (Scheme 4). The transformation to a compound offormula (XIa) may be performed by reacting the intermediate of formula(Xa) with ammonia, optionally in the presence of an oxidation agent,such as tert-butyl hydroperoxide.

Method (v): Formation of a Corresponding Compound of Formula (XI):

A ketone of formula (III), is reacted with ethanebis(thioamide) inpresence of ammonia to form a compound of formula (XIII) (Scheme 5).Said reaction may be performed at a temperature range between roomtemperature and +180° C., in a suitable solvent, such as methanol,ethanol or isopropyl alcohol.

An alkylating agent, such as methyl iodide and a thioimidazole offormula (XIII) are reacted to form a compound of formula (XIV) (Scheme5). Said compound (XIV) may be further transformed into a compound offormula (XI), wherein R¹ is an alkyl group such as methyl or ethyl, byreacting it with an organometallic reagent, such as methylmagnesiumbromide or ethylmagnesium bromide, in the presence of a suitablecatalyst, such as [1,3-bis(diphenylphosphino)propane]nickel(II)chloride. Alternatively, the compound of formula (XI) (re is an alkylsuch as methyl or ethyl) may also be obtained by reacting compound offormula (XIV) with a mixture of zinc iodide and a Grignard reagent suchas methylmagnesium bromide, or ethylmagnesium bromide, in the presenceof a suitable catalyst such as bis(triphenylphosphine)palladium(II)chloride in a suitable solvent such as THF, 2-methyl-tetrahydrofuran ortoluene.

Method (vi) Formation of a Corresponding Compound of Formula (XI):

An imine of formula (VIII), is reacted with ethanebis(thioamide) to forma compound of formula (XIII) (Scheme 6). Said reaction may be performedat a temperature range between +120° C. and +180° C., in a suitablesolvent, such as methanol, ethanol or isopropyl alcohol. An alkylatingagent, such as methyl iodide and a thioimidazole of formula (XIII) arereacted to form a compound of formula (XIV) (Scheme 6). Said compound(XIV) may be further transformed into a compound of formula (XI),wherein R¹ is an alkyl group such as methyl or ethyl, by reacting itwith an organometallic reagent, such as methylmagnesium bromide orethylmagnesium bromide, in the presence of a suitable catalyst, such as[1,3-bis(diphenylphosphino)propane]nickel(II) chloride. Alternatively,the compound of formula (XI) (R¹ is an alkyl such as methyl or ethyl)may also be obtained by reacting compound of formula (XIV) with amixture of zinc iodide and a Grignard reagent such as methylmagnesiumbromide, or ethylmagnesium bromide, in the presence of a suitablecatalyst such as bis(triphenylphosphine)palladium(II) chloride in asuitable solvent such as THF, 2-methyl-tetrahydrofuran or toluene.

Method (vii) Formation of a Corresponding Compound of Formula (XV):

A compound of formula (XV) may be obtained by reacting a compound offormula (III) with a compound of formula (XVI) (Scheme 7), wherein R¹¹is alkyl (such as for example tert-butyl). The reaction is performed inthe presence of a suitable Lewis acid, such as a compound of formula(XVII), wherein R¹² is alkyl (such as ethyl or isopropyl). The reactionis performed in a suitable solvent (such as dichloromethane,2-methyl-tetrahydrofuran or tetrahydrofuran) at a temperature betweenroom temperature and reflux temperature, optionally with azeotropicdistillation to remove an alcohol formed in the reaction.

Method (viii) Formation of a Corresponding Compound of Formula (XVIII):

A compound of formula (XIX) may be obtained by reacting a compound offormula (III) with hydroxylamine hydrochloride and a base such aspotassium acetate in a suitable solvent such as a mixture of water and asuitable alcohol such as ethanol at reflux temperature (Scheme 8). Saidcompound (XIX) may be further transformed into a compound of formula(XVIII) by reacting it with a compound of formula (XX), wherein R¹³ isalkyl or aryl. The reaction is performed in a suitable solvent such asdichloromethane in the presence of triethylamine at a temperaturebetween −78° C. and room temperature.

Method (ix) Formation of a Corresponding Compound of Formula (XXI):

A compound of formula (XXI) wherein R¹⁴ is an alkyl such as methyl maybe obtained by reacting a compound of formula (III) with a siliconcompound such as LiHMDS in a suitable solvent such as dichloromethane,2-methyl-tetrahydrofuran or tetrahydrofuran (Scheme 9).

Method (x) Formation of a Corresponding Compound of Formula (XIa):

A compound of formula (VIII) may be obtained by reacting a compound(XXIII) (wherein PG is a protecting group such as for example S(O)R¹¹(Method (vii), formula XV), SiR¹⁴ (such as SiMe₃) (Method (ix), formulaXXI), P(O)(R¹³)₂) (Method (viii), formula XVIII), S(O)₂alkyl,C(O)Oalkyl, OH or Oalkyl using a suitable method of removing theprotecting group PG to form imine (VIII) (Scheme 10). A suitable methodmay be, but is not limited to, treating said compound XXIII with an acidsuch as hydrochloric acid under dry conditions in a suitable solvent(such as dioxane or tetrahydrofuran), or treatment with a protic solventsuch as methanol (when PG=SiMe₃). Compound (VIII) may be isolated orreacted further without isolation. A compound of formula (VIII) isfurther reacted with 2-oxopropane thioamide (described in Asinger et al.Justus Liebigs Annalen der Chemie 1971, vol 744, p. 51-64) optionally inthe presence of triethyl orthoformate, in a solvent such as methanol ata temperature between room temperature and reflux temperature,optionally under Dean-Stark conditions, to yield a compound of formula(Xa). The transformation to a compound of formula (XIa) may be performedby reacting the intermediate of formula (Xa) with ammonia, optionally inthe presence of an oxidation agent, such as tert-butyl hydroperoxide. If2-oxopropane thioamide is exchanged for 2-oxobutanethioamide in theprocess described by Scheme 10, the compounds of formula (Xb) and (XIb)will be obtained instead of (Xa) and (XIa).

Method (xi) Formation of a Corresponding Compound of Formula (XIa):

A compound of formula (Xa) may be obtained from a compound of formula(VIII) (Scheme 11). An imine of formula (VIII) is reacted with2-oxopropane thioamide (described in Asinger et al. Justus LiebigsAnnalen der Chemie 1971, vol 744, p. 51-64) in a solvent such asmethanol at a temperature between room temperature and refluxtemperature to yield a compound of formula (Xa). Compound (VIII) may beobtained from a ketone of formula (III) (Scheme 4) or prepared bymethods known to the person skilled in the art. The compound of formula(Xa) is subsequently treated with ammonia, to yield the compound offormula (XIa). If 2-oxopropane thioamide is exchanged for2-oxobutanethioamide in the process described by Scheme 11, thecompounds of formula (Xb) and (XIb) will be obtained instead of (Xa) and(XIa) (see above).

Method (xii) Formation of a Corresponding Compound of Formula (XIa):

A compound of formula (XXIII) (wherein PG is a protecting group such asfor example S(O)R¹¹ (Method (vii), formula XV), SiR¹⁴ (such as SiMe₃,Method (ix), formula XXI), P(O)(R¹³)₂) (Method (viii), formula XVIII),S(O)₂alkyl, C(O)Oalkyl, OH or Oalkyl is reacted with 2-oxopropanethioamide (described in Asinger et al. Justus Liebigs Annalen der Chemie1971, vol 744, p. 51-64) in a solvent such as acetonitrile at atemperature range between +100° C. and +160° C. to yield a compound offormula (Xa) (Scheme 12). The compound of formula (Xa) is subsequentlytreated with ammonia, in a suitable solvent such as methanol, THF, or2-methyl-tetrahydrofuran optionally in the presence of an oxidationagent, such as tert-butyl hydroperoxide, at a temperature between roomtemperature and 150° C., optionally in a closed system, to yield thecompound of formula (XIa). If 2-oxopropane thioamide is exchanged for2-oxobutanethioamide in the process described by Scheme 12, thecompounds of formula (Xb) and (XIb) (see above) will be obtained insteadof (Xa) and (XIa).

Method (xiii) Formation of a Corresponding Compound of Formula (XI):

A compound of formula (XXIII), wherein PG is a protecting group such asfor example S(O)R¹¹ (Method (vii), formula XV), SiR¹⁴ (such as SiMe₃)(Method (ix), formula XXI), P(O)(R¹³)₂) (Method (viii), formula XVIII),S(O)₂alkyl, C(O)Oalkyl, OH or Oalkyl, is reacted withethanebis(thioamide) to form a compound of formula (XIII) (Scheme 13).Said reaction may be performed at a temperature range between refluxtemperature and +180° C., in a suitable solvent, such as methanol,ethanol or isopropyl alcohol, optionally in the presence of ammonia. Analkylating agent, such as methyl iodide and a thioimidazole of formula(XIII) are reacted to form a compound of formula (XIV) (Scheme 13). Saidcompound (XIV) may be further transformed into a compound of formula(XI), wherein R¹ is an alkyl group such as methyl or ethyl, by reactingit with an organometallic reagent, such as methylmagnesium bromide orethylmagnesium bromide, in the presence of a suitable catalyst, such as[1,3-bis(diphenylphosphino)propane]nickel(II) chloride. Alternatively,the compound of formula (XI) (R¹ is an alkyl such as methyl or ethyl)may also be obtained by reacting compound of formula (XIV) with amixture of zinc iodide and a Grignard reagent such as methylmagnesiumbromide, or ethylmagnesium bromide, in the presence of a suitablecatalyst such as bis(triphenylphosphine)palladium(II) chloride in asuitable solvent such as THF, 2-methyl-tetrahydrofuran or toluene.

Method (xiv) Formation of a Corresponding Compound of Formula (I):

A compound of formula (I) wherein R² is an optionally substituted arylor heteroaryl, may be obtained (Scheme 14) by starting from, forexample, a compound of formula (XXIV), and reacting said compound offormula (XXIV) with a boronic acid or a boronic ester or a stannane offormula T-R², wherein T is for example B(OH)₂, B(Oalkyl)₂, or SnR₃, andR² is an optionally substituted aryl or a heteroaryl, in the presence ofa transition metal catalyst such as a palladium catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride,tetrakis(triphenylphosphine)-palladium(0), palladiumdiphenylphosphinoferrocene dichloride, palladium(II) acetate orbis(dibenzylideneacetone) palladium (0), or sodium tetrachloropalladate(II). Optionally, a suitable ligand such as triphenylphosphine,tri-tert-butylphosphine or 2-(dicyclohexylphosphino)biphenyl,3-(di-tert-butylphosphonium)propane sulfonate, or zinc and sodiumtriphenylphosphinetrimetasulfonate, is used. A suitable base, such ascesium fluoride, an alkyl amine, such as triethyl amine, or an alkalimetal or alkaline earth metal carbonate or hydroxide such as potassiumcarbonate, sodium carbonate, cesium carbonate, or sodium hydroxide, maybe used in the reaction. Said reaction may be performed in a suitablesolvent, such as toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran,dioxane, dimethoxyethane, water, ethanol, N,N-dimethylacetamide,acetonitrile or N,N-dimethylformamide, or mixtures thereof.Alternatively a compound of formula (I) wherein R² is an optionallysubstituted aryl or heteroaryl can be prepared from compound (XXIV) bytransformation into a compound (Ia) wherein T is as described above(B(OH)₂ or B(Oalkyl)₂) (Scheme 14a). Compound (Ia) is then reacted witha compound R²-LG wherein R² is an optionally substituted aryl orheteroaryl and LG is a leaving group such as a halogen to yield compound(I).

Method (xv) Formation of a Corresponding Compound of Formula (I):

A compound of formula (I), wherein R² is cyano, may be obtained (Scheme14) by starting from, for example, a compound of formula (XXIV), whereinLG is a leaving group such as a halogen, (such as iodide, bromide orchlorine), and reacting said compound of formula (XXIV) with a metalcyano reagent such as copper(I) cyanide.

Method (xvi) Formation of a Corresponding Compound of Formula (I):

A compound of formula (I), wherein R² is an alkyl group such as methylmay be generated from a compound of formula (XXIV) (Scheme 14), whereinLG represents a leaving group, such as a halogen, (such as iodide,bromide or chlorine), by reaction with an organometallic reagentgenerated from zinc iodide and methylmagnesium bromide under theinfluence of a transition metal catalyst such as for examplebis(triphenylphosphine)palladium(II) chloride.

Method (xvii) Formation of a Corresponding Compound of Formula (I):

A compound of formula (I), wherein R² is an alkyne may be generated froma compound of formula (XXIV) (Scheme 14), wherein LG represents aleaving group, such as a halogen, (such as iodide or bromide), byreaction with an alkyne such as such as an alkylethyne or acycloalkylethyne under the influence of a transition metal catalyst suchas for example tetrakis(triphenylphosphine)palladium(0) in presence of abase such as triethylamine and copper(I)iodide. The alkyne is optionallysilylated. Said reaction may be performed at a temperature range betweenroom temperature and reflux temperature, in a suitable solvent, such asTHF or toluene.

Method (xviii) Formation of a Corresponding Compound of Formula (I):

A compound of formula (I) wherein R² is NHC(O)R⁹ may be preparedaccording to Scheme 14 by reacting a compound of formula (XXIV) with acompound R⁹C(O)NH₂ in the presence of a suitable palladium catalyst suchas palladium(II) acetate, optionally in the presence of a suitableligand such as Xantphos. Said reaction is preformed in the presence of asuitable base such as cesium carbonate in a suitable solvent such as THFor 2-methyl-tetrahydrofuran at a temperature between reflux temperatureand 160° C.

Method (xix) Formation of a Corresponding Compound of Formula (I):

A compound of formula (I) wherein R² is NHC(O)R⁹ may be obtained from acompound of formula (XXIV) as shown in Scheme 15.

A compound of formula (XXIV) is reacted with ammonia in the presence oftrans-4-hydroxy-L-proline, potassium carbonate and copper(I)iodide in asolvent such as DMSO at a temperature between room temperature and 150°C. to give a compound of formula (XXV). Said compound of formula (XXV)is further reacted with a carboxylic acid of formula (XXVI) wherein R⁹is as defined above. The reaction is performed in the presence of asuitable amide coupling agent such as1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide in a solvent such as DMF,optionally in the presence of hydrochloric acid.

Method (xx) Formation of a Corresponding Compound of Formula (IIIb):

A compound of formula (IIIb) may be obtained by reacting a ketone offormula (XII) with an aldehyde or ketone of formula (XXII) in presenceof a base such as pyrrolidine, piperidine, proline, morpholine or Boraxin a suitable solvent such as benzene, toluene, methanol or ethanol or amixture of water and a suitable alcohol such as methanol or ethanol in atemperature range between room temperature and +180° C. (Scheme 16).

Method (xxi) Formation of a Compound of Formula (I)

A compound of formula (I) wherein R² is OR⁸ may be prepared by reactinga compound of formula (XXIV), wherein LG represents a leaving group,such as a halogen, (such as iodide or bromide), with an alcohol offormula (XXVII) in the presence of a suitable palladium catalyst such aspalladium(II) acetate, optionally in the presence of a suitable ligandsuch as 2-(di-t-butylphosphino)-1,1′-binaphthyl (Scheme 17). Saidreaction is performed in the presence of a suitable base such as cesiumcarbonate in a suitable solvent such as THF, 2-methyl-tetrahydrofuran ortoluene at a temperature between 20° C. and 160° C.

Method (xxii) Formation of a Compound of Formula (II)

A compound of formula (IT) wherein R² is OR⁸ may be prepared by reactinga compound of formula (XXVIII), with a compound of formula (XXIX),wherein LG represent a suitable leaving group, such as halogen (such aschloride, bromide, or iodide), or trifluoromethylsulphonate, in thepresence of a suitable base such as an alkali carbonate, such as Cs₂CO₃,K₂CO₃, Na₂CO₃, in a suitable solvent such as THF, 2-methyl-THF, DMF, orDMSO, or a mixture thereof, at a temperature between 0-150° C. (Scheme18).

Method (xxiii) Formation of a Compound of Formula (II)

A compound of formula (II) wherein R² is OR⁸ may be prepared by reactinga compound of formula (XXVIII), with a compound of formula (XXVII), inthe presence of a suitable phosphine source such as triphenyl phosphine,in the presence of a suitable activating reagent such as diethylazodicarboxylate, in a suitable solvent such as THF, 2-methyl-THF, orDMF or a mixture thereof, at a temperature of 0-100° C. (Scheme 19).

Method (xxiv) Formation of a Compound of Formula (XXX)

A compound of formula (Villa) may be obtained by for example method(vii) and method (x) as shown in Scheme 20. Said compound of formula(Villa) may be obtained by reacting a compound (XVa), with an acid suchas hydrochloric acid under dry conditions in a suitable solvent (such asdioxane or tetrahydrofuran). Compound (Villa) may be isolated or reactedfurther without isolation. The compound of formula (Villa) is furtherreacted with 2-oxopropane thioamide (described in Asinger et al. JustusLiebigs Annalen der Chemie 1971, vol 744, p. 51-64) optionally in thepresence of triethyl orthoformate, in a solvent such as methanol at atemperature between room temperature and reflux temperature, optionallyunder azeotropic distillation conditions, to yield a compound of formula(Xc). A compound of formula (Xd) may be obtained by reacting a compoundof formula (Xa) with a suitable fluorinating agent such as a compound offormula (XXXI) under the influence of cuprous iodide in a suitablesolvent, such as acetonitrile, at a temperature between room temperatureand reflux temperature.

The transformation to a compound of formula (XXX) may be performed byreacting the compound of formula (Xd) with ammonia, optionally in thepresence of an oxidation agent, such as tert-butyl hydroperoxide.

Compounds of formula (II), (III), (V), (VI), (XII), (XVI), (XVII), (XX),(XXII), (XXVI), and (XXVII) are commercially available compounds, or areknown in the literature, or they are prepared by standard processesknown in the art.

General Methods

All solvents used were of analytical grade and commercially availableanhydrous solvents were routinely used for reactions. Starting materialsused were available from commercial sources, or prepared according toliterature procedures. Room temperature refers to 20-25° C. Solventmixture compositions are given as volume percentages or volume ratios.

Microwave heating was performed in a Biotage Creator, Initiator or SmithSynthesizer Single-mode microwave cavity producing continuousirradiation at 2450 MHz. It is understood that microwaves can be usedfor the heating of reaction mixtures.

Thin layer chromatography (TLC) was performed on Merck TLC-plates(Silica gel 60 F₂₅₄) and and spots were UV visualized. Straight phaseflash column chromatography (“flash chromatography”) was manuallyperformed on Merck Silica gel 60 (0.040-0.063 mm), or automaticallyusing an ISCO Combiflash® Companion™ system using RediSep™ normal-phaseflash columns using the solvent system indicated. Phase separation wasoptionally performed on an Isolute® phase separator.

NMR

NMR spectra were recorded on a 400-600 MHz NMR spectrometer fitted witha probe of suitable configuration. Spectra were recorded at ambienttemperature unless otherwise stated. Chemical shifts are given in ppmdown- and upfield from TMS (0.00 ppm). The following reference signalswere used in ¹H-NMR: TMS δ 0.00, or the residual solvent signal ofDMSO-d₆ δ 2.49, CD₃OD δ 3.30, acetone-d₆ 2.04 or CDCl₃ δ 7.25 (unlessotherwise indicated). Resonance multiplicities are denoted s, d, t, q,m, br and app for singlet, doublet, triplet, quartet, multiplet, broadand apparent, respectively. In some cases only diagnostic signals arereported.

HPLC, HPLCMS, and LCMS Analyses:

High pressure liquid chromatography (HPLC) was performed on a reversedphase (RP) column. A linear gradient was applied using for examplemobile phase A (10 mM NH₄OAc in 5% CH₃OH or 5% CH₃CN (aq.), or 0.1% NH₃(aq.) or 0.1% formic acid (aq.)) and B (CH₃OH or CH₃CN). Massspectrometry (MS) analyses were performed in positive and/or negativeion mode using electrospray ionization (ESI+/−) and/or atmosphericpressure chemical ionization (APCI+/−).

GCFID and GCMS Analyses:

Gas chromatography (GC) was performed on a GC equipped with a massspectrometer (MS) or a flame ionization detector (FID). The MS ionsource was either an electron impact (EI) or a chemical ionization (CI,reactant gas methane). For separation a capillary column was used forexample DB-5MS, (J&W Scientific). A linear temperature gradient wasapplied.

Preparative Chromatography:

Preparative chromatography was run on a Waters FractionLynx system witha Autosampler combined Automated Fraction Collector (Waters 2767),Gradient Pump (Waters 2525), Column Switch (Waters CFO) and PDA (Waters2996). Column; XBridge® Prep C8 10 μm OBD™ 19×300 mm, with guard column;XTerra® Prep MS C8 10 μm 19×10 mm Cartridge. A gradient of A (95% 0.1 MNH₄OAc in MilliQ water and 5 MeCN) in B (100% MeCN) or a gradient of A(95% 0.1 M NH₄OAc in MilliQ water and 5% MeOH), A (0.2% NH₃ in MilliQwater) or A (0.2% formic acid in MilliQ water) in B (100% MeOH) wasapplied for LC-separation at flow rate 20 ml/min. Preparative chiralchromatography for separation of isomers was run on for example anLaPrep® system using the specified column and mobile phase system.

SFC Analyses:

Supercritical Fluid Chromatography (SFC) was performed on a straightphase column. A isocratic flow was applied using mobile phase A (CO₂)and for example mobile phase B (MeOH, EtOH or IPA).

Straight Phase HPLC Analyses:

High pressure liquid chromatography (HPLC) was performed on a straightphase column. A linear gradient or isocratic flow was applied using forexample mobile phase A (Heptane) and B (EtOH or IPA).

High-Resolution Mass Spectrometry (HRMS) for accurate mass measurementswas performed on a Waters Synapt-G2 mass spectrometer equipped with aLockSpray source and connected to an Acquity UPLC system with a PDAdetector and an Acquity UPLC BEH C18 column. The measured mass confirmedthe elemental composition within 3 ppm.

Abbreviations

-   ACN acetonitrile-   aq aqueous-   Atm atmospheric pressure-   Boc t-butoxycarbonyl-   Borax di-sodium tetraborate or sodium borate or sodium tetraborate-   Cbz benzyloxycarbonyl-   CDI 1,1′-carbonyldiimidazole-   dba dibenzylideneacetone-   DCM dichloromethane-   DEA diethylamine-   DIBAL-H diisobutylaluminium hydride-   DIPEA diisopropylethylamine-   DME 1,2-dimethoxyethane-   DMF N,N-dimethyl formamide-   DMSO dimethyl sulfoxide-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   eq. or equiv. equivalent-   h hour(s)-   HPLC high performance liquid chromatography-   IPA isopropanol-   LCMS liquid chromatography mass spectrometry-   LiHMDS lithium bis(trimethylsilyl)amide-   MeOH methanol-   min minute(s)-   MS mass spectrometry-   MW microwave(s)-   NH₄OAc ammonium acetate-   NMR nuclear magnetic resonance-   ox oxidation-   Psi pounds per square inch-   quant. quantitative-   RCM ring closing metathesis-   r.t. room temperature-   sat. saturated-   SFC supercritical fluid chromatography-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMEDA tetramethylethylenediamine-   UPLC ultra performance liquid chromatography-   2-Me THF 2-methyl tetrahydrofuran

Compounds have been named using CambridgeSoft MedChem ELN v2.2 orACD/Name, version 10.0, or 10.06, or version 12.01, software fromAdvanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada,www.acdlabs.com, or Lexichem, version 1.9, software from OpenEye.

EXAMPLES

Below follows a number of non-limiting examples of compounds of theinvention.

Intermediate 1N-(6-Bromochroman-4-ylidene)-2-methylpropane-2-sulfinamide

6-Bromochroman-4-one (5.0 g, 22 mmol) and 2-methylpropane-2-sulfinamide(2.6 g, 22 mmol) were dissolved in dry THF (80 mL). Titanium ethoxide(10 g, 44 mmol) was added. The resulting mixture was heated at 60° C.for 2 days. An additional portion of titanium ethoxide (1.0 g, 8.4 mmol)was added after 12 h. The mixture was mixed with heptane and evaporatedonto silica gel. Flash chromatography on silica (0-50% EtOAc in heptane)gave the title compound (6.0 g, 83% yield). ¹H NMR (500 MHz, CDCl₃) δppm 1.34 (s, 9H) 3.26-3.32 (m, 1H) 3.47-3.54 (m, 1H) 4.28-4.40 (m, 2H)6.83 (d, 1H) 7.46 (dd, 1H) 8.06 (d, 1H); MS (ES+) m/z 330 [M+H]⁺.

Intermediate 2 2-Oxopropanethioamide

A solution of acetyl cyanide (140 mL, 1764.24 mmol) in2-methyl-tetrahydrofuran (850 mL) was stirred at −10° C. as hydrogensulfide (Sigma-Aldrich lecture bottle) was bubbled through the solution.The addition of hydrogen sulfide was stopped after 15 min and to thestirred mixture, triethylamine (1.230 mL, 8.82 mmol) in2-methyl-tetrahydrofuran (13 mL) was added slowly over 30 min(exothermic reaction). Hydrogen sulfide addition was continued for 3 hat 5° C., 3 h at 10° C. and overnight at 15° C. Nitrogen gas was bubbledthough the solution for 30 min, followed by evaporation of thevolatiles. To the residue was added a mixture of heptane (100 mL) andEtOAc (100 mL). A solid was filtered off (79 g, 43% yield) and thefiltrate was purified by a short-plug silica gel chromatography, elutingwith 50% ethylacetate in heptane to give 79 g (43% yield) of the titlecompound. Both crops (in total 158 g, 87% yield) contained the titleproduct of adequate purity according to GC-MS: MS (ES+) m/z 104 [M+H]⁺.

Intermediate 36-Bromo-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione

N-(6-Bromochroman-4-ylidene)-2-methylpropane-2-sulfinamide (2.0 g, 6.0mmol, Intermediate 1) was dissolved in dry dioxane (2 mL), and 4M HCl indioxane (15 mL, 60.00 mmol) was added. A white precipitate started toform. The mixture was stirred at r.t. for 12 h. The mixture was dilutedwith dry Et₂O (50 mL) and vacuum filtered. The filter cake was washedwith dry Et₂O (50 mL), then immediately dissolved by shaking in NaHCO₃(aq) and CH₂Cl₂. The organic phase was dried (K₂CO₃) and evaporated togive 6-bromochroman-4-imine (1.3 g, 5.7 mmol). The solid was dissolvedtogether with 2-oxopropanethioamide (Intermediate 2, 1.7 g, 17 mmol,Intermediate 2) in dry methanol (5 mL) and the resulting solution washeated at 60° C. for 12 h. Evaporation onto silica and purification byflash chromatography (EtOAc in heptane) gave the title compound (0.39 g,21% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 2.18 (m, 1H), 2.35 (m, 1H),2.42 (s, 3H), 4.35-4.40 (m, 1H), 4.60 (m, 1H), 6.81 (d, 1H), 6.88 (d,1H), 7.33 (dd, 1H); MS (ES+) m/z 311 [M+H]⁺.

Intermediate 4 6-Bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione (0.10 g,0.32 mmol, Intermediate 3) was dissolved in MeOH (1 mL) and 7M ammoniain MeOH (4 mL, 28 mmol) was added. The solution was heated at 60° C. for12 h in a sealed vial. The solution was evaporated in vacuo. Thetreatment with 7M ammonia was repeated in the same way one more time.Evaporation in vacuo gave the title compound (73 mg, 77% yield) whichwas used without further purification in the following step. ¹H NMR (400MHz, CDCl₃) δ ppm 2.11 (m, 2H), 2.35 (s, 3H), 4.53 (m, 2H), 4.98 (br s,2H), 6.66 (m, 1H), 6.78 (d, 1H), 7.22 (m, 1H); MS (ES+) m/z 294 [M+H]⁺.

Intermediate 5 6′-Bromo-4-methoxy-spiro[cyclohexane-1,2′-indane]-1′-oneMethod A Step 1: 6′-Bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

Potassium tert-butoxide (7.50 g, 66.81 mmol) was added in portions to6-bromo-2,3-dihydro-1H-inden-1-one (11.75 g, 55.67 mmol) and methylacrylate (11.05 mL, 122.5 mmol) in THF (55 mL) under cooling in anice-bath. The mixture was stirred for 1.5 h at r.t. Water (80 mL) andKOH (3.12 g, 55.7 mmol) was added and the mixture was heated to 75° C.and then at 60° C. overnight. The mixture was cooled to 0° C., and theformed precipitate was filtered off and dried in vacuo to give the titlecompound (11.69 g, 72% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 1.83-1.92(m, 2H), 2.15-2.27 (m, 2H), 2.40-2.50 (m, 2H), 2.71 (dt, 2H), 3.17 (s,2H), 7.39 (d, 1H), 7.75 (dd, 1H), 7.92 (d, 1H); MS (ES+) m/z 293 [M+H]⁺.

Step 2: 6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

6′-Bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 5Step 1, 6.1 g, 20.8 mmol) was dissolved in THF (220 mL) and cooled to−65° C. Sodium borohydride (0.354 g, 9.36 mmol) was added and thecooling bath was removed. The mixture was allowed to reach 0° C.(approx. 30 min). Water (10 mL) was added, and most of the organicsolvent was removed by evaporation. The residue was partitioned betweenEtOAc (100 mL), and an aq. solution of NaCl (50 mL). The organic phasewas dried (MgSO₄) and evaporated to give a product which was combinedwith additional product obtained in a similar way starting from 14.6 gof 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione. Purificationwas made by flash chromatography (120 g silica, gradient elution: CH₂Cl₂to CH₂Cl₂/MeOH (90:10)) affording 13.6 g (66% yield) of the titlecompound. The obtained material consisted of an 80:20 mixture of isomer1 and isomer 2. Analytical samples of the isomers were isolated by flashchromatography (heptane/EtOAc gradient) to yield:

Isomer 1:(1r,4r)-6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.43 (m, 4H), 1.49-1.62 (m, 2H),1.79-1.89 (m, 2H), 2.99 (s, 2H), 3.39-3.50 (m, 1H), 4.68 (d, 1H), 7.56(d, 1H), 7.76 (d, 1H), 7.85 (dd, 1H); MS (ES+) m/z 317 [M+Na]⁺ and

Isomer 2:(1s,4s)-6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.20 (m, 2H), 1.51-1.63 (m, 2H),1.65-1.76 (m, 2H), 1.93 (td, 2H), 2.98 (s, 2H), 3.83 (d, 1H), 4.45 (d,1H), 7.51-7.55 (m, 1H), 7.76 (d, 1H), 7.84 (dd, 1H); MS (ES+) m/z 317[M+Na]⁺.

Step 3: 6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

A mixture of isomers of6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Step 2, 12.7 g, 43.0 mmol) was dissolved in THF (210 mL)under N₂ and cooled to 0° C. Potassium tert-butoxide (5.79 g, 51.6 mmol)was added portionwise and the mixture was stirred at 0° C. for 25 min.Methyl iodide (4.30 mL, 68.8 mmol) was added. The cooling bath wasremoved, and the mixture was stirred at r.t. Additional potassiumtert-butoxide (0.483 g, 4.30 mmol) was added twice, after 2 h and 3 hrespectively, and then the mixture was stirred for 2 h. Water (100 mL)was added and the resulting solution was partitioned between aq. NaClsolution (200 mL), and EtOAc (200 mL). The aq. phase was extracted withanother portion of EtOAc (100 mL). The combined organic phases weredried (MgSO₄) and evaporated to give 12.5 g (94% yield) of a mixture(approx. 80:20) of:

Isomer 1:(1r,4r)-6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

and Isomer 2:(1s,4s)-6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

¹H NMR (400 MHz, DMSO-d₆, signals for Isomer 1) δ ppm 1.20-1.32 (m, 2H),1.40-1.48 (m, 2H), 1.51-1.62 (m, 2H), 1.97-2.07 (m, 2H), 3.00 (s, 2H),3.15-3.23 (m, 1H), 3.26 (s, 3H), 7.56 (d, 1H), 7.77 (d, 1H), 7.86 (dd,1H); MS (ES+) m/z 309 [M+H]⁺.

Method B Step 1: 6′-Bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

6-Bromo-2,3-dihydro-1H-inden-1-one (800 g, 3.79 mol) and methyl acrylate(787 mL, 8.72 mol) in 2-methyl-tetrahydrofuran (4 L) were stirred at 28°C. Potassium tert-pentoxide solution in toluene (1.7 M, 2.68 L, 4.55mol) was added dropwise keeping the temperature between 30° C. and 43°C. The mixture was stirred for 0.5 h at 25° C. Water (4 L) was added andafter 10 min were KOH (383 g, 6.82 mol) added. The mixture was heated toreflux and the organic solvent was distilled off during 4 h. The mixturewas cooled to 10° C., and the formed precipitate was filtered off anddried in vacuo to give the title compound (837 g, 75% yield). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.74-1.85 (m, 2H), 1.94 (m, 2H), 2.34 (m, 2H),2.52-2.60 (m, 2H), 3.27 (s, 2H), 7.60 (d, 1H), 7.79-7.83 (m, 1H), 7.89(m, 1H); MS (ES+) m/z 293 [M+H]^(|).

Step 2:(1r,4r)-6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

To 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate5 Step 1, 50.52 g, 172.3 mmol) in DCM (250 mL), borane tert-butylaminecomplex (5.70 g, 65.49 mmol) in DCM (50 mL) was slowly charged at 0° C.After 40 min concentrated HCl (20 mL) followed by 20% NaCl (70 mL) werecharged. The mixture was allowed to reach r.t. and was stirred for 30min. The phases were separated and to the water phase were DCM (40 mL)and H₂O (10 mL) charged. The organic phases were combined, concentratedand dried under vacuum overnight to give the title product (52.4 g, 100%yield) as a mixture of the title product (83% yield) and the otherdiasteromer(1s,4s)-6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(17%): ¹H NMR (500 MHz, CDCl₃, signals for both isomers) δ ppm ¹H NMR(500 MHz, CDCl₃) δ ppm 1.39-1.50 (m, 3H), 1.67-1.85 (m, 3H) 2.05-2.12(m, 2H) 2.96 (s, 0.34H), 2.98 (s, 1.68H), 3.76 (m, 0.83H), 4.04 (m,0.17H), 7.34 (m, 1H) 7.70 (m, 1H) 7.88 (d, 1H); MS (ES+) m/z 295 [M+H]⁺.

Step 3:(1r,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

(1r,4r)-6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Step 2, 50.9 g, 172 mmol) (containing 17% of(1s,4s)-6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one),methyl iodide (18.33 mL, 293.1 mmol) and 2-Me THF (360 mL) were heatedto 30° C. under N₂. Potassium tert-pentoxide solution in toluene (1.7 Min toluene, 203 mL, 344 mmol) was added dropwise over 30 min. Themixture was allowed to reach r.t. and was stirred for 1 h. Water (250mL) was added and after 10 min of stirring the phases were separated.The organic phase was washed with water (140 mL), concentrated and driedin vacuo to give a solid. 300 mL MeOH was added to the solid and themixture was heated to reflux. Water was added (30 mL) followed by refluxfor 5 min. The mixture was slowly allowed to reach r.t. The mixture wasstirred overnight at r.t. The solid was filtered off to give the titlecompound as a single isomer (31 g, 58% yield): ¹H NMR (500 MHz, CDCl₃) δppm 1.38 (m, 2H) 1.52 (m, 2H) 1.77 (td, 2H) 2.16 (m, 2H) 2.98 (s, 2H)3.28 (m, 1H) 3.40 (s, 3H) 7.35 (d, 1H) 7.70 (dd, 1H) 7.88 (d, 1H); MS(ES+) m/z 309 [M+H]⁺.

Method C Step 1: 6′-Bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

Methyl acrylate (6.6 L, 73 mol) was charged gradually in three equalportions (each 2.2 L, 24.6 mol) to a mixture of 6-bromo-1-indanone (8.00kg, 37.9 mol), THF (16 L) and potassium tert-butoxide (210 g, 1.87 mol)at approximately 20-30° C. Additional potassium tert-butoxide (86 g,0.77 mol), dissolved in THF (0.39 L), was charged after the firstportion of methyl acrylate. More potassium tert-butoxide (86 g, 0.77mol), dissolved in THF (0.39 L), was charged after the second portion ofmethyl acrylate. Further potassium tert-butoxide (4.64 kg, 41.3 mol)solution in THF (21 L) was then charged gradually at approximately20-30° C. Solvent (21.5 L) was distilled off at approximately 65° C. andthen a mixture of water (49 L) and 50%. aq KOH (2.3 L, 30 mol) was addedover approximately 10 min. at below 60° C. The reaction was held at 60°C. for approximately 6 h., then cooled to 20° C. over 1 h. and thenfiltered after holding at 20° C. for approximately 12 h. The solids werewashed with a mixture of water (8 L) and THF (4 L), and then dried togive the title compound (7.47 kg, at 92% w/w NMR assay, 23.4 mol, 62%yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.78-1.84 (m, 2H), 1.95 (td,2H), 2.32-2.38 (m, 2H), 2.51-2.59 (m, 2H), 3.27 (s, 2H), 7.60 (d, 1H),7.81 (m, 1H), 7.89 (m, 1H).

Step 2:(1r,4r)-6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 5Step 1, 750 g, 2.56 mol) and propan-2-ol (9.855 L) were heated to refluxand ground NaOH (100 g, 2.50 mol) was added in two portions to themixture. The mixture was heated to reflux for 2 h. 5 L of solvent wereremoved by vacuum distillation. Toluene (2 L) was added and 2 L ofsolvent was removed by vacuum distillation. Toluene (3 L) followed by 2M HCl (1.278 L, 2.56 mol) was added to the mixture under stirring. Thephases were separated and the organic phase was washed with water (2.0L). The organic phase was concentrated and toluene (2 L) was added andthen the mixture was concentrated. 2-methyl-tetrahydrofuran (1 L) wasadded and then 0.5 L of the solvent was removed by vacuum distillation,the resulting mixture was used as such in the next step. The titlecompound was a mixture with the diastereomer(1s,4s)-6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one inthe ratio 7:3 (established by HPLC and NMR analysis): ¹H NMR (500 MHz,CDCl₃, signals for both isomers) δ ppm 1.40-1.52 (m, 3H), 1.70-1.84 (m,3H), 2.04-2.11 (m, 2H), 2.97 (s, 0.62H), 3.00 (s, 1.38H), 3.73-3.81 (m,0.7H), 4.04 (m, 0.3H), 7.31-7.38 (m, 1H), 7.67-7.73 (m, 1H), 7.89 (m,1H).

Step 3:(1r,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

Borane tert-butylamine complex (820 g, 9.4 mol) dissolved in DCM (3.6 L)was charged to a slurry of6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 5Step 1, 7.46 kg, at 92% w/w NMR assay, 23.4 mol) in DCM (41 L) atapproximately 0-5° C. over approximately 40 min. After approximately 1h., a solution of NaCl (2.68 kg), water (12.9 L) and 37% hydrochloricacid (2.5 L, 31 mol) was charged. The mixture was warmed toapproximately 15° C. and the phases separated after settling intolayers. The DCM phase, containing(1r,4r)-6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Step 2), was returned to the reactor, together withmethyl methanesulfonate (2.59 L, 30.5 mol) and tetrabutylammoniumchloride (130 g, 0.47 mol). Aq. 50% NaOH (13 L, 229 mol) was thencharged to the vigorously agitated reaction mixture over approximately 1h. at approximately 20° C. After holding for approximately 16 h., water(19 L) was added and the aq. phase discarded after separation. Solvent(34 L) was distilled off at atmospheric pressure and then more solvent(20 L) was distilled off whilst adding EtOH (20 L) in 5 equal portions.EtOH (14 L) was added and the solution cooled to 25° C. A sample (0.3 L)was taken at 40° C. during the cooling. The sample crystallisedspontaneously and was recharged to the reactor at 25° C. Afterre-heating to approximately 40° C., water (14 L) was charged overapproximately 20 min. The slurry was cooled to approximately 20° C. andheld for 16 h. before filtering. The solids were washed with a mixtureof water (4.8 L) and EtOH (6.4 L) and then dried to give the titlecompound (containing 4.6% of Isomer 2:(1s,4s)-6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one byHPLC-analysis) (5.57 kg, at 91% NMR assay, 16.4 mol, 70% yield): ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.22-1.32 (m, 2H), 1.41-1.48 (m, 2H), 1.56 (td,2H), 1.99-2.07 (m, 2H), 3.01 (s, 2H), 3.16-3.23 (m, 1H), 3.27 (s, 3H),7.56 (d, 1H), 7.77 (d, 1H), 7.86 (dd, 1H).

Intermediate 106-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-one

A solution of potassium tert-butoxide (3.94 g, 35.1 mmol) in t-BuOH (35mL) was added dropwise over 15 min to a solution of 6-bromo-1-indanone(3.53 g, 16.73 mmol) in 2-methyl-tetrahydrofuran (350 mL) at r.t. undera nitrogen atmosphere. After 15 min bis(2-bromoethyl) ether (2.102 mL,16.73 mmol) was added and the resulting mixture was stirred at r.t. for5 h. Potassium tert-butoxide (0.938 g, 8.36 mmol) was added and themixture was stirred at r.t. overnight. The mixture was quenched withsaturated aq. NH₄Cl (150 mL) and the organic layer was separated. Theaqueous layer was extracted with EtOAc (3×50 mL) and Et₂O (50 mL). Thecombined organics were washed with brine (100 mL), dried over MgSO₄,filtered and concentrated. The resulting residue was taken up in DCM,concentrated onto silica gel and purified on a silica gel column elutedwith 0-40% EtOAc in heptane to give 1.14 g (24% yield) of the titlecompound; MS (ES+) m/z 281 [M+H]⁺.

Intermediate 116′-Bromo-4,4-difluoro-spiro[cyclohexane-1,2′-indane]-1′-one

A solution of 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione(Intermediate 5 Method A Step 1, 2 g, 6.82 mmol) in DCM (10 mL) wasadded to a solution of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride(FLUOLEAD™) (3.24 g, 13.0 mmol) and EtOH (0.159 mL, 2.73 mmol) in DCM(10 mL) at 0° C. The reaction mixture was allowed to reach r.t. and wasstirred overnight. The reaction mixture was poured into a cooled aq. 1 MNaOH solution (5 mL) and the mixture was stirred for 60 min at r.t. Thewater phase was extracted with DCM twice. The combined organic phaseswere concentrated and the crude product was purified on a silica column(gradient of EtOAc/n-heptane 0-20%). Two batches were collected. Batch 1gave 2.2 g (purity by HPLC, uv detection 42%) and batch 2 gave 819 mg(purity by HPLC, uv detection 62%). The compound was used as such innext step. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.57-1.66 (m, 2H), 1.83-1.98(m, 2H), 2.00-2.08 (m, 2H), 2.26-2.38 (m, 2H), 3.01 (s, 2H), 7.35 (d,1H), 7.72 (dd, 1H), 7.89 (d, 1H).

Intermediate 125-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexane]-3-one Step 1:2-(5-Bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile

To a solution of 5-bromo-2-fluoro-benzaldehyde (30.45 g, 150 mmol) inTHF (250 mL), was added DMAP (0.203 g, 1.73 mmol) followed bytrimethylsilyl cyanide (18.24 g, 183.8 mmol). The reaction mixture wasstirred at r.t. for 4 h and then concentrated in vacuo to afford 45.8 g(quantitative yield) of the title compound which was used directly inthe next step without further purification. ¹H NMR (400 MHz, CDCl₃): δppm 1.71 (m, 6H), 2.31 (m, 2H), 3.32 (m, 1H), 3.41 (s, 3H), 7.03 (d,J=9.20 Hz, 1H), 7.36 (t, J=8.80, 2.00 Hz, 1H), 7.77 (d, J=2.00 Hz, 1H).

Step 2: (5-Bromo-2-fluorophenyl)(1-hydroxy-4-methoxycyclohexyl)methanone

LiHMDS (1.0 M, 165 mL, 165 mmol) was added dropwise to a solution of2-(5-bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile(Intermediate 12 Step 1, 45.80 g, 150 mmol) in acetonitrile (250 mL) at−78° C. The reaction mixture was stirred for 1.5 h and a solution of4-methoxycyclohexanone (Lee, C. K.; Lee, I.-S. H.; Noland, W. E.Heterocycles, 2007, 71, 419-428) (20.3 g, 150 mmol) in THF (30 mL) wasadded slowly and the stirring at −78° C. was continued for 3 h. 1M HClaq. (300 mL) was added at −78° C., and the mixture was allowed to warmslowly to r.t. and stirred overnight. The phases were separated and theaqueous layer was extracted with EtOAc (2×500 mL). The combined extractswere dried over Na₂SO₄, filtered, and concentrated in vacuo to afford 57g of the crude material. A portion of the crude product (30 g) waspurified by flash chromatography using a gradient of 0 to 50% EtOAc inEtOAc in hexanes to afford 9.24 g of the title compound.

Step 3: 5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one

A mixture of(5-bromo-2-fluorophenyl)(1-hydroxy-4-methoxycyclohexyl)methanone(Intermediate 12 Step 2, 1.05 g, 3.17 mmol) and potassium tert-butoxide(0.445 g, 3.80 mmol) in THF (10 mL) was heated in a microwave reactor at70° C. for 30 min. The solvent was removed in vacuo and the residue waspurified by flash chromatography using a gradient of 0 to 15% EtOAc inhexanes to afford 388 mg (39% yield) of the title compound. ¹H NMR (400MHz, CDCl₃): δ ppm 1.71 (m, 6H), 2.31 (m, 2H), 3.32 (m, 1H), 3.41 (s,3H), 7.03 (d, J=9.20 Hz, 1H), 7.36 (t, J=8.80, 2.00 Hz, 1H), 7.77 (d,J=2.00 Hz, 1H); MS (ES+) m/z 312 [M+H]^(|).

Intermediate 14 3-Bromo-5-(prop-1-ynyl)pyridine

3,5-Dibromopyridine (30 g, 127 mmol), copper(I) iodide (7.24 g, 38.0mmol) and tetrakis(triphenylphosphine)palladium(0) (4.39 g, 3.80 mmol)were mixed in toluene (120 mL) under nitrogen atmosphere.1-(Trimethylsilyl)-1-propyne (26.36 mL, 164.5 mmol), triethylamine (53.0mL, 380 mmol) and tetra-n-butylammonium fluoride (12.66 mL, 12.66 mmol)were added. The mixture was heated to reflux and stirred under nitrogenovernight. Water (100 mL) was added to the reaction mixture was filteredand the phases separated. The organic phase was washed with 1 M HCl aq.(100 mL). The organic phase was concentrated and dissolved in MeOH (200mL), filtered and concentrated. The mixture was dissolved in DCM andevaporated with silica gel to dryness, and then transferred to a silicagel column (300 g). The product was eluted with a gradient of EtOAc(0-5%) in heptane. The fractions containing the pure product wascombined and evaporated to give the title compound (16.39 g, 66% yield):¹H NMR (500 MHz, CDCl₃) δ ppm 2.08 (s, 3H), 7.82 (t, 1H), 8.52 (d, 1H),8.55 (d, 1H); MS (APCI+) m/z 197.0 [M+H]^(|).

Intermediate 15 5-(Prop-1-ynyl)pyridin-3-ylboronic acid

3-Bromo-5-(prop-1-ynyl)pyridine (Intermediate 14, 25 g, 117 mmol),2-methyl-tetrahydrofuran (60 mL), toluene (200 mL) and triisopropylborate (33.2 mL, 140.78 mmol) were mixed. The mixture was cooled to −50°C. To the cold mixture was added n-BuLi (59.8 mL, 149.5 mmol) dropwiseduring 30 min. The mixture was stirred for 60 min. at −50° C. 2M HCl aq.(100 mL) was added. The mixture was then allowed to reach r.t. andstirred for 20 min. The organic and water phase were separated. Theorganic phase was extracted with NaOH (2M aq.) (2×100 mL). The waterphases were combined and the pH was adjusted to pH 5. The product wasextracted with 2-methyl-THF (2×100 mL). The organic phase was dried withNa₂SO₄, filtered and concentrated to give the title compound (16.47 g,87% yield): ¹H NMR (500 MHz, CD₃OD) δ ppm 2.11 (s, 3H) 8.21 (br. s., 1H)8.53 (m, 2H); MS (APCI+) m/z 162.2 [M+H]⁺.

Intermediate 16 2-Bromo-4-(prop-1-ynyl)pyridine

To a solution of 2-bromo-4-iodopyridine (2 g, 7.04 mmol), copper(I)iodide (0.080 mL, 2.11 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.407 g, 0.35 mmol) in toluene(85 mL) was added 1-(trimethylsilyl)-1-propyne (1.054 mL, 7.04 mmol),triethylamine (3.24 mL, 23.25 mmol) and tetrabutylammonium fluoride (1 Min THF, 7.04 mL, 7.04 mmol) and the resulting mixture was stirred underan argon atmosphere at r.t. overnight. The mixture was concentrated andthe resulting residue was partitioned between water (10 mL) and DCM (10mL) and poured into a phase separator. The organic phase was collected,and the aqueous phase was extracted once with DCM (10 mL). The combinedorganics were concentrated and purified by flash chromatography using 0%to 30% EtOAc in heptane to give the title compound (1.195 g, 87% yield):¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.11 (s, 3H), 7.42 (dd, 1H), 7.65 (s,1H), 8.35 (dd, 1H); MS (ES+) m/z 196 [M+H]⁺; MS (APCI+) m/z 196 [M+H]⁺.

Intermediate 17 4-(Prop-1-ynyl)-2-(trimethylstannyl)pyridine

2-Bromo-4-(prop-1-ynyl)pyridine (Intermediate 16, 1.077 g, 5.49 mmol)was dissolved in toluene (30 mL) and 1,1,1,2,2,2-hexamethyldistannane(2.278 mL, 10.99 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.635 g, 0.55 mmol) were added. The reaction was to stirred at 80° C.overnight under argon atmosphere. The mixture was cooled to r.t. andfiltered through a pad of diatomaceous earth and concentrated in vacuo.Toluene (20 mL) was added and the mixture was concentrated in vacuo toyield the title compound that was used as such in the next step: MS(APCI+) m/z 282 [M+H]⁺.

Intermediate 18 Methyl 5-(but-2-ynyloxy)picolinate

To a solution of but-2-yn-1-ol (0.635 mL, 8.49 mmol) in THF (30 mL) wereadded methyl 5-hydroxypicolinate (1.3 g, 8.49 mmol), triphenylphosphine(3.34 g, 12.73 mmol) and diisopropyl azodicarboxylate (2.507 mL, 12.73mmol) at 0° C. The reaction mixture was then allowed to reach r.t andstirred for 2 days. The reaction mixture was concentrated and theproduct was purified by flash chromatography using a heptane/EtOAcgradient to give 1.42 g (82% yield) of the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 1.87 (t, 3H), 4.00 (s, 3H), 4.79 (q, 2H), 7.41 (dd,1H), 8.11-8.20 (m, 1H), 8.49 (d, 1H).

Intermediate 19 5-(But-2-ynyloxy)picolinic acid

To a solution of methyl 5-(but-2-ynyloxy)picolinate (Intermediate 18,1.42 g, 6.92 mmol) in THF (15 mL) was added lithium hydroxide (0.871 g,20.76 mmol) dissolved in water (5 mL) to the reaction mixture at r.t.After 3 days of stirring was the reaction mixture partioned betweenwater and EtOAc. The water was made acidic with aq. solution of HCl (2M)and extracted with EtOAc. The organic phase was dried over MgSO₄ andconcentrated to give 0.60 g (45% yield) of the title compound: ¹H NMR(500 MHz, CD₃OD) δ ppm 1.84 (t, 3H), 4.87 (q, 2H), 7.57 (dd, 1H), 8.14(d, 1H), 8.34 (d, 1H); MS (ES+) m/z 192 [M+H]⁺.

Intermediate 266-Bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-one

A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (8.2 g, 38.13 mmol),dihydro-pyran-3-one (4.96 g, 49.57 mmol) and pyrrolidine (4.12 mL, 49.57mmol) in toluene (80 mL) was stirred at 50° C. for 1 h. The temperaturewas increased to reflux, and the reaction was refluxed for 22 h.Additional dihydro-pyran-3-one (0.5 g 5 mmol) was added and the mixturewas refluxed for an additional 24 h. The mixture was allowed to reachr.t., and then water (50 mL) followed by EtOAc (100 mL) was added. Theorganic layer was concentrated and the residue was purified by flashchromatography using a gradient of heptane to 40% EtOAc in heptane togive the title compound (9 g, 79% yield): ¹H NMR (500 MHz, CDCl₃) δ ppm1.57 (m, 1H), 1.72 (ddd, 1H), 1.96 (m, 1H), 2.12 (m, 1H), 2.71 (m, 2H),3.51 (d, 1H), 3.58 (m, 1H), 3.86 (m, 2H), 6.96 (d, 1H), 7.57 (dd, 5H),7.97 (d, 4H); MS (ES+) m/z 297 [M+H]⁺.

Intermediate 27 6-Bromo-2-tetrahydropyran-3-yl-chroman-4-one

A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (18 g, 83.70 mmol),tetrahydro-2H-pyran-3-carbaldehyde (9.55 g, 83.70 mmol) and pyrrolidine(6.95 mL, 83.70 mmol) in MeOH (125 mL) was heated to reflux for 4.5 h.The mixture was allowed to reach r.t. and concentrated. The residue wasdissolved in EtOAc (150 mL) and washed with 1M NaOH (80 mL), 1M HCl (80mL), and brine (80 mL) successively. The organic phase was concentrated,the residue was purified by flash chromatography with a gradient of 10%EtOAc in heptane to 40% EtOAc in heptane to give the title compound (18g, 69% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.50 (m, 3H), 1.79 (m,0.5H), 1.94 (m, 1.5H), 2.67 (m, 1H), 2.86 (m, 1H), 3.30 (m, 2H), 3.78(m, 1H), 3.84 (m, 0.5H), 4.04 (dd, 0.5H), 4.44 (m, 1H), 7.05 (dd, 1H),7.71 (m, 1H), 7.79 (d, 1H); MS (ES+) m/z 311 [M+H]⁺.

Intermediate 286-Bromo-2-(2,2-dimethyltetrahydropyran-4-yl)chroman-4-one

A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (13.5 g, 62.78 mmol),2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (9.40 g, 62.78 mmol) andpyrrolidine (5.22 mL, 62.78 mmol) in MeOH (125 mL) was heated to refluxfor 3 h. The mixture was allowed to reach r.t. and then concentrated.The residue was dissolved in EtOAc (100 mL) and washed with 1M NaOH (60mL), 1M HCl (60 mL), and brine (60 mL) successively. The organic phasewas concentrated and the residue was purified by flash chromatographywith a gradient of 10% EtOAc in heptane to 40% EtOAc in heptane to givethe title compound (16.22 g, 76% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.15 (m, 6H), 1.26 (m, 2H), 1.52 (m, 1H), 1.76 (m, 1H), 2.12 (ddd, 1H),2.65 (m, 1H), 2.83 (m, 1H), 3.57 (m, 1H), 3.66 (m, 1H), 4.32 (ddd, 1H),7.05 (dd, 1H), 7.70 (dd, 1H), 7.78 (d, 1H); MS (ES−) m/z 337 [M−H].

Intermediate 29 2-Oxobutanethioamide

Hydrogen sulfide was bubbled through a solution of propionyl cyanide (25g, 300.88 mmol) in 2-methyl-tetrahydrofuran (200 mL) at −10° C. for 10min. The addition of hydrogen sulfide was stopped and triethyl amine(0.419 mL, 3.01 mmol, as a solution in 2-methyl-tetrahydrofuran (4 mL))was added dropwise over 10 min. Hydrogen sulfide addition was continuedfor 1.5 h at −10° C. before the addition was stopped and the flask wasflushed with nitrogen for 2.5 h, during which time the reaction mixturewas allowed to reach rt. The mixture was concentrated and the resultingresidue was taken up in 1:1 EtOAc:heptane and passed through a shortplug of silica to give 30.2 g (86% yield) of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.99 (t, 3H), 2.93 (q, 2H), 9.79 (br. s., 1H),10.20 (br. s., 1H); MS (ES+) m/z 118 [M+H]⁺.

Intermediate 30 5′-Methylspiro[chroman-4,2′-imidazole]-4′,6-diamine

A mixture of 6-bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine(Intermediate 4, 115 mg, 0.39 mmol), trans-4-hydroxy-L-proline (51 mg,0.39 mmol), CuI (37 mg, 0.20 mmol), and K₂CO₃ (162 mg, 1.17 mmol) inDMSO (0.9 mL) was stirred at r.t. for 15 min. Ammonia, (30-33% in H₂O,0.37 mL, 5.86 mmol) was added and the mixture was subjected to microwaveirradiation at 110° C. for 3 h. The mixture was diluted with DMSO andwater and filtered through a pad of diatomaceous earth. NaCl (s) wasadded and the aqueous mixture was extracted with EtOAc (5×35 mL). Thecombined organic phases were dried (Na₂SO₄) and evaporated to give acrude product which was purified by flash chromatography (4 g silica,eluent: CHCl₃/(MeOH/NH₃) gradient) affording the title compound (59 mg,65% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.76-1.92 (m, 2H), 2.19 (s,3H), 4.18-4.34 (m, 2H), 4.45 (br. s., 2H), 5.69 (d, 1H), 6.35 (dd, 1H),6.45 (br. s., 2H), 6.50 (d, 1H); MS (ES+) m/z 231 [M+11]

Intermediate 31 1-Bromo-3-(prop-1-ynyl)benzene

To a solution of 1-bromo-3-iodobenzene (3.0 g, 10.6 mmol), copper(I)iodide (0.61 g, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.61 g, 0.53 mmol) in toluene (20 mL) was added1-(trimethylsilyl)-1-propyne (1.6 mL, 10.6 mmol), triethylamine (4.9 mL,35.0 mmol) and a 1M solution of tetrabutylammonium fluoride intetrahydrofuran (10.6 mL, 10.6 mmol). The resulting mixture was stirredunder a nitrogen atmosphere at r.t. overnight. The mixture waspartitioned between water and Et₂O and the organic phase was dried overmagnesium sulfate and concentrated in vacuo. The residue was filteredthrough a plug of silica and eluted with heptane (4×25 mL) affording thetitle compound (1.6 g, 80% yield): ¹H NMR (500 MHz, DMSO-d₆) ppm 2.05(s, 3H), 7.30 (t, 1H), 7.39 (d, 1H), 7.52-7.56 (m, 1H), 7.56-7.58 (m,1H); MS (CI) m/z 195 [M+H]⁺.

Intermediate 32 2-Chloro-4-(prop-1-ynyl)pyridine

4-Bromo-2-chloropyridine (1.00 g, 5.20 mmol),1-(trimethylsilyl)-1-propyne (0.846 mL, 5.72 mmol), copper(I) iodide (99mg, 0.52 mmol), and tetrakis(triphenylphosphine)palladium(0) (90 mg,0.08 mmol) were taken up in toluene (14 mL) in a microwave vial.Tetra-N-butylammonium fluoride (1M in THF) (6 mL, 6.00 mmol) was addedand the reaction vessel was sealed and heated at 100° C. for 20 min in amicrowave reactor. After cooling, the mixture was filtered throughdiatomaceous earth, and then concentrated in vacuo. The product waspurified by flash chromatography using a gradient of EtOAc in heptane(0-50%) to give the title compound (530 mg, 67% yield): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.11 (s, 3H), 7.38 (dd, 1H), 7.51 (s, 1H), 8.37 (d, 1H);MS (ES+) m/z 152 [M+H]⁺.

Intermediate 33 4-Bromo-2-(prop-1-ynyl)pyridine

The title compound (0.560 g, 57% yield) was prepared as described forIntermediate 32 starting from 4-bromo-2-iodopyridine (1.42 g, 5.00mmol): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.08 (s, 3H), 7.63 (dd, 1H), 7.73(d, 1H), 8.39 (d, 1H); MS (MM-ES+APCI)+ m/z 196 [M+H]^(|).

Intermediate 34 3-(Prop-1-ynyl)phenylboronic acid

n-Butyl lithium (2.5 M in hexanes, 3.7 mL, 9.4 mmol) was added dropwiseto a solution of 1-bromo-3-(prop-1-ynyl)benzene (Intermediate 31, 1.66g, 8.51 mmol) and triisopropyl borate (2.2 mL, 9.4 mmol) intetrahydrofuran (5 mL) and toluene (15 mL) at −78° C. under an argonatmosphere. The reaction mixture was stirred for 30 min. and thenallowed to reach r.t. and stirred for 1 h. The mixture was cooled to−78° C., and 3 M aq. hydrochloric acid was added and the mixture wasstirred at r.t. for 15 min. The mixture was basified by addition ofsolid KOH. 2-methyl-tetrahydrofuran was added under stirring and theobtained solid was collected by filtration affording the title compound1.0 g (75% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.01 (s, 3H),6.92-7.03 (m, 1H), 7.09-7.20 (m, 1H), 7.55-7.79 (m, 2H).

Intermediate 353-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A suspension of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (665 mg,2.62 mmol), 3-chloro-5-iodobenzonitrile (345 mg, 1.31 mmol), andpotassium acetate (386 mg, 3.93 mmol) in dioxane (5 mL) was degassedwith a stream of argon for a couple of min. PdCl₂(dppf) CH₂Cl₂ (53.5 mg,0.07 mmol) was added and the mixture was heated at reflux under N₂ for 4h. The mixture was allowed to cool and was then filtered. The filtercake was washed with EtOAc. The filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography (eluent: heptane/EtOAcgradient) affording the title compound (69 mg, 20% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.30 (s, 12H), 7.88 (dd, 1H), 7.90-7.94 (m, 1H),8.19 (dd, 1H); MS (CI) m/z 264 [M+H]⁺.

Note: the product has no UV-response but is visualized on TLC by avisualization agent containing phosphomolybdic acid and Ce(SO₄)₂.

Intermediate 36 5-(But-2-ynyloxy)pyrazine-2-carboxylic acid

To a slurry of 5-chloro-pyrazine-2-carboxylic acid (0.79 g, 5.00 mmol)in DMF (35 mL) were added 2-butyn-1-ol (3.74 mL, 50.0 mmol) andpotassium tert-butoxide (2.24 g, 20.0 mmol). The resulting mixture washeated at 65° C. overnight. The reaction mixture was neutralized with 2M HCl and then concentrated in vacuo. A part (400 mg) of the crudematerial was partitioned between 0.5 M NaOH and a 1:1 mixture of heptaneand EtOAc. The aqueous phase was made slightly acidic (pH-3-4) byaddition of 1 M HCl. To the obtained suspension was added NaCl (s) andthe mixture was extracted twice with EtOAc. The combined organic phaseswere dried (Na₂SO₄) and evaporated to give 0.11 g of the title compound.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.84 (t, 3H), 5.06 (q, 2H), 8.42 (d,1H), 8.82 (d, 1H), 13.38 (br. s., 1H); MS (ES⁺) m/z 193 [M+H]⁺.

Intermediate 37 1-(4-Bromo-2-iodobenzyl)cyclobutanecarbonitrile

Lithium diisopropylamide (3.34 mL, 6.68 mmol), was added dropwise to asolution of cyclobutanecarbonitrile (0.417 g, 5.14 mmol) in THF (20 mL)at −78° C. under an argon atmosphere. The reaction mixture was stirredat −78° C. for 30 min, then was a solution of4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J.Org. Chem. 2011, 76, 2227-2239, 2.51 g, 6.68 mmol) in THF (8 mL) slowlyadded dropwise and the reaction was to allowed to reach r.t. The mixturewas stirred for another 3 h and then quenched with water. The reactionmixture was partitioned between water and EtOAc, the organic layer wasdried over MgSO₄ and concentrated to give a crude product which waspurified by flash chromatography (eluent: heptane/ethylacetate 12:1) toafford the title compound (1.71 g, 89% yield): ¹H NMR (500 MHz, CDCl₃) δppm 2.08-2.34 (m, 4H), 2.47-2.58 (m, 2H), 3.18-3.23 (m, 2H), 7.29 (s,1H), 7.49 (dd, 1H), 8.03 (d, 1H); GC MS (EI) m/z 375 M^(+•).

Intermediate 38 6′-Bromospiro[cyclobutane-1,2′-inden]-1′(3′H)-one

A dried flask charged with1-(4-bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37, 2.60g, 6.91 mmol), was dissolved in dry THF (100 mL) under an argonatmosphere. The resulting mixture was cooled to −78° C. and then wastert-butyllithium (1.7 M in pentane, 8.13 mL, 13.83 mmol), addeddropwise. The reaction was stirred for 1.5 h at −78° C. and then thereaction was quenched with MeOH (0.5 mL), followed by aq. hydrochloricacid (2M, 10 mL). The resulting solution was concentrated to remove theorganic solvent and then partitioned between DCM and water. The organicphase was dried over MgSO₄ and concentrated to give a crude productwhich was purified by flash chromatography (eluent:heptane/EtOAc20:1-15:1-10:1) to afford the title compound (1.1 g, 63%yield): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.97-2.13 (m, 3H), 2.13-2.24 (m,1H), 2.45-2.60 (m, 2H), 3.24 (s, 2H), 7.31 (d, 1H), 7.67 (dd, 1H), 7.88(d, 1H); GC MS (EI) m/z 250 M^(+•).

Intermediate 396′-(Cyclobutylmethoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3 g, 20.3 mmol)in THF (140 mL) were cyclobutylmethanol (2.10 mL, 22.3 mmol),triphenylphosphine (7.97 g, 30.4 mmol) and diisopropyl azodicarboxylate(5.98 mL, 30.4 mmol) added. The mixture was heated to 45° C. and leftstirring over the weekend. The crude product was purified by flashchromatography using a gradient of 0-10% EtOAc in heptane to afford 2.56g (58% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃) δ ppm1.81-2.03 (m, 4H), 2.11-2.20 (m, 2H), 2.69-2.74 (m, 2H), 2.78 (dt, 1H),3.04-3.12 (m, 2H), 3.96 (d, 2H), 7.17-7.22 (m, 2H), 7.36 (d, 1H); MS(ES+) m/z 217 [M+H]⁺.

Intermediate 40(1r,4r)-6′-(Cyclobutylmethoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

6′-(Cyclobutylmethoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione(Intermediate 39, 2.35 g, 7.88 mmol) was dissolved in tetrahydrofuran(40 mL) and MeOH (3.19 mL, 78.76 mmol). Borane-trimethylamine complex(1.26 g, 17.3 mmol) was added and the mixture was stirred at r.t.overnight. Citric acid monohydrate (23.2 g, 110 mmol) was added in allat once, followed by dropwise addition of water (2.84 mL, 157 mmol). Themixture was stirred for 4 h. before being diluted with water andextracted with EtOAc twice. The combined organic phases were washed withNaHCO₃ and brine, and concentrated. The crude product was purified on asilica gel column (gradient elution 0-50% EtOAc in n-heptane) to givethe title compound (1.84 g, 78% yield, containing 29% of(1s,4s)-6′-(cyclobutylmethoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one).The compound was used as such in the next step: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.10 (m, minor isomer), 1.2-1.4 (m, 4H), 1.57 (m, 2H),1.71 (m, minor isomer), 1.75-1.95 (m, 6H), 2.07 (m, 2H), 2.71 (m, 1H),2.92 (m, 2H), 3.44 (m, 1H), 3.84 (m, minor isomer), 3.98 (d, 2H), 4.42(d, minor isomer), 4.66 (d, 1H), 7.07 (d, 1H), 7.26 (m, 1H), 7.44 (m,1H); MS (ES+) m/z 301.1 [M+H]⁺.

Intermediate 41 3-Bromo-5-chloro-2-methylpyridine

2,3-Dibromo-5-chloropyridine (1.3 g, 4.70 mmol), methylboronic acid(0.30 g, 5.01 mmol), bis(triphenylphosphine)palladium(II) chloride (0.50g, 0.70 mmol) and dioxane (10 mL) were added. K₂CO₃ (2 M aq. solution,7.0 mL, 14.0 mmol) was added and the reaction was put under N₂ (g)atmosphere. The reaction was heated to reflux for 5 h. The reaction wasstirred at 50° C. overnight and then heated to reflux for additionally 1h. Methylboronic acid (0.14 g, 2.35 mmol) was added and the reaction wasrefluxed for 4 h and the allowed to cool down to r.t. The mixture wasfiltered through a silica plug. EtOAc and water were added and thephases were separated. The organic phase was washed two more times withwater. The organic phase was dried with MgSO₄, filtered and concentratedin vacuo. The crude product was purified by flash chromatography (12 gSiO₂, 0-20% MeOH containing 0.1 M NH₃ in DCM). The fractions containingpure product were pooled and concentrated, yielding the title compound(123 mg, 13% yield): ¹H NMR (DMSO-d₆) δ ppm 2.56 (s, 3H), 8.29 (d, 1H),8.52 (d, 1H); MS (CI) m/z 206 [M+H]⁺.

Intermediate 42 Diethyl 2-(5-bromo-3-chloropyridin-2-yl)malonate

Diethyl malonate (0.87 mL, 5.7 mmol) was added dropwise to a suspensionof NaH (55% in mineral oil, 0.27 g, 6.2 mmol) in DMF (6 mL) at 0° C. Theice-bath was removed and the mixture was stirred under N₂ at r.t. for 20min. 5-Bromo-2,3-dichloropyridine (1.0 g, 4.4 mmol) was added, and themixture was stirred at 120° C. overnight. The mixture was allowed tocool and was then partitioned between water containing NaCl and EtOAc.The organic phase was dried (MgSO₄) and evaporated to give a crudeproduct which was purified by flash chromatography (25 g SiO₂,heptane/EtOAc gradient) affording the title compound (0.8 g, 2 mmol, 52%yield) containing a residue of unreacted malonic ester. MS (ES+) m/z 350[M+H]⁺. A part of this material was used as such in the subsequent step.

Intermediate 43 5-Bromo-3-chloro-2-methylpyridine

A solution of impure diethyl 2-(5-bromo-3-chloropyridin-2-yl)malonate(Intermediate 42, 0.41 g, 1.2 mmol) and conc. aq. HCl (3 mL) was heatedat reflux for 3 h. The volatiles were removed in vacuo, and the residuewas co-evaporated with acetonitrile. The residual solid(mono-decarboxylated acid) was dissolved in dioxane (4.5 mL) and heatedat reflux overnight. The volatiles were removed in vacuo. The residuewas purified by flash chromatography (4 g SiO₂, heptane/EtOAc gradient)affording the title compound (0.12 g, 51% yield): ¹H NMR (500 MHz,CDCl₃) δ ppm 2.60 (s, 3H), 7.82 (d, 1H), 8.46 (d, 1H); MS (CI) m/z 206[M+H]⁺.

Intermediate 443-Chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A suspension of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.836 g,3.29 mmol), 5-bromo-3-chloro-2-methylpyridine (Intermediate 43, 0.34 g,1.65 mmol), and potassium acetate (0.485 g, 4.94 mmol) in dioxane (5 mL)was degassed with a stream of N₂ (g) for a couple of min. PdCl₂(dppf)CH₂Cl₂ (0.067 g, 0.08 mmol) was added and the mixture was heated atreflux under N₂ (g) for 1.5 h. The mixture was allowed to cool to r.t.and was then filtered. The filter cake was washed with EtOAc. Thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography (40 g SiO₂, gradient elution with 0-80% EtOAc in heptaneto yield the title compound (0.44 g, quantitative yield): ¹H NMR (500MHz, CDCl₃) δ ppm 1.35 (s, 12H), 2.65 (s, 3H), 7.95-8.03 (m, 1H), 8.69(d, 1H); MS (ES+) m/z 172 [M+H]⁺ (mass corresponding to the boronicacid).

Intermediate 45 3-Bromo-4-methyl-5-(prop-1-ynyl)pyridine

3,5-Dibromo-4-methylpyridine (0.50 g, 2.0 mmol),1-(trimethylsilyl)-1-propyne (0.35 mL, 2.4 mmol), copper(I) iodide (0.11g, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.02mmol) were mixed in toluene (2 mL). The mixture was degassed by a streamof argon for a couple of min. Tetra-n-butylammonium fluoride (1 M inTHF) (2.4 mL, 2.4 mmol) was added, and the reaction was heated under N₂at 70° C. overnight. The mixture was partitioned between watercontaining sat aq. NaHCO₃ and EtOAc. The organic phase was dried (MgSO₄)and evaporated to give a crude product which was purified by flashchromatography (40 g SiO₂, heptane/EtOAc gradient) affording the titlecompound (0.067 g, 16% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.15 (s,3H), 2.46 (s, 3H), 8.48 (s, 1H), 8.61 (s, 1H); MS (ES⁺) m/z 210 [M+H]⁺.

Intermediate 46(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

(1r,4r)-6′-(Cyclobutylmethoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 40, containing 29% of an isomer, 1.84 g, 6.13 mmol) wasdissolved in 2-Me THF (17 mL) under an inert atmosphere and the solutionwas cooled to 0° C. Methyl iodide (0.498 mL, 7.96 mmol) was addedfollowed by portionwise addition of potassium tert-butoxide (0.962 g,8.58 mmol). The resulting mixture was stirred at 35° C. for 1 h.Potassium tert-butoxide (0.962 g, 8.58 mmol) was added and stirringcontinued. After another 30 min, a new portion of potassiumtert-butoxide (0.103 g, 0.92 mmol) was added and stirring continued.After a total of 4 h, full conversion was obtained. Water (6 mL) andbrine (3 mL) was added. The phases were separated and the organic layerwas dried and concentrated. The crude product was purified on a silicagel column (gradient elution of 0-50% EtOAc in n-heptane) to give thetitle compound (1.480 g, 77%). The product contained 29% of(1s,4s)-6′-(cyclobutylmethoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-oneand was used as such in next step: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11(m, minor isomer), 1.26 (m, 2H), 1.40 (d, 1H), 1.57 (m, 2H), 1.75-1.95(m, 5H), 2.0-2.1 (m, 3H), 2.71 (m, 1H), 2.95 (s, 3H), 2.95 (s, minorisomer), 3.19 (m, 1H), 3.24 (s, minor isomer), 3.26 (s, 3H), 3.45 (m,minor isomer), 3.99 (d, 2H), 7.07 (d, 1H), 7.26 (m, 1H), 7.45 (m, 1H);MS (ES+) m/z 315.1 [M+H]⁺.

Intermediate 47 6-(3,3,3-trifluoropropoxy)-2,3-dihydro-1H-inden-1-one

To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20.3 mmol)in THF (140 mL) were triphenylphosphine (7.97 g, 30.4 mmol) and3,3,3-trifluoropropan-1-ol (1.963 mL, 22.27 mmol) added. Diisopropylazodicarboxylate (5.98 mL, 30.4 mmol) was added dropwise and the mixturewas left stirring at r.t. overnight. Since there was starting materialremaining, 3,3,3-trifluoro-1-propanol (0.892 mL, 10.1 mmol) was addeddropwise and stirring was continued. After 30 min the mixture was heatedto 40° C. and after 1 h the mixture was concentrated. The crude productwas purified by flash chromatography (0-12% EtOAc in heptane as eluent)to afford 1.08 g (22% yield) of the title compound (containing somediisopropyl azodicarboxylate): ¹H NMR (500 MHz, CDCl₃) δ 2.65 (qt, 2H),2.71-2.77 (m, 2H), 3.05-3.13 (m, 2H), 4.23 (t, 2H), 7.17-7.23 (m, 2H),7.40 (d, 1H); MS (ES+) m/z 245 [M+H]⁺.

Intermediate 48 3-Bromo-5-(but-1-ynyl)-pyridine

But-1-yne (g) was during 5 min gently bubbled through anhydrousacetonitrile cooled in an ice-water bath. The resulting solutioncontained about 170 mg but-1-yne per mL. The solution of but-1-yne (4.57mL, 14.36 mmol) and diisopropylamine (3.72 mL, 26.11 mmol) were addedsequentially to a mixture of 3,5-dibromopyridine (3.09 g, 13.06 mmol),bis(triphenylphosphine)-palladium(II) chloride (0.458 g, 0.65 mmol) andCuI (0.249 g, 1.31 mmol) in acetonitrile (15 mL) under an argonatmosphere. The resulting mixture was stirred at r.t. overnight, dilutedwith EtOAc and passed through a short plug of silica. The solvents wereevaporated and the residue was purified by flash chromatography onsilica (gradient elution 0-20% EtOAc in heptane) to give 2.40 g of thetitle compound (87% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (t,4H), 2.47 (q, 3H), 8.11 (t, 1H), 8.57 (d, 1H), 8.65 (d, 1H); MS (ES+)m/z 210 [M+H]⁺.

Intermediate 49 5-(But-1-ynyl)pyridin-3-ylboronic acid

n-BuLi (2.5 M in hexanes, 5.46 mL, 13.7 mmol) was added dropwise to asolution of 3-bromo-5-(but-1-ynyl)pyridine (Intermediate 48, 2.39 g,11.4 mmol) and triisopropyl borate (3.15 mL, 13.65 mmol) in 2-Me THF (20mL) at −50° C. The mixture was stirred for 1.5 h while the temperaturewas kept between −50 and −40° C. The mixture was lifted up from thecooling bath and 2 M aq. HCl (12 mL, 24 mmol) was added followed bystirring for 20 min. The mixture was diluted with EtOAc. Aq. NaOH (2 M)was added until pH about 12 was obtained in the aqueous phase. Thephases were separated. The organic phase was extracted with dilute aq.NaOH and with water. The combined aqueous phases were washed with EtOAc,acidified to pH about 5 by the addition of conc. HCl and extracted withDCM. The organic phase was dried over Na₂SO₄ and concentrated to give1.522 g (76% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃) δ ppm1.11-1.37 (m, 3H), 2.26-2.58 (m, 2H), 7.46-10.34 (m, 3H); MS (ES+) m/z176 [M+H]⁺.

Intermediate 50 3-Bromo-5-methylbenzonitrile

A mixture of 1,3-dibromo-5-methylbenzene (1.0 g, 4.0 mmol), coppercyanide (0.179 g, 2.00 mmol), pyridine (0.323 mL, 4.00 mmol), and DMF(15 mL) were heated at 190° C. for 10 h in microwave reactor. Thereaction mixture was allowed to cool to r.t., and then poured into asolution of H₂O (20 mL) and aq. NH₃ solution (25-35% NH₃, 10 mL) and thewater phase was extracted with EtOAc. The combined organic extracts weredried (Mg₂SO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (hexane/EtOAc gradient elution) toafford the title compound (0.58 g, 74% yield): ¹H NMR (500 MHz, CDCl₃) δppm 2.39 (s, 3H) 7.41 (s, 1H) 7.58 (s, 1H) 7.60 (s, 1H); MS (EI) m/z 195M⁺.

Intermediate 51 1-(4-Bromo-2-iodobenzyl)cyclopropanecarbonitrile

The title compound (2.1 g, 55% yield) was prepared as described for1-(4-Bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37)starting from cyclopropanecarbonitrile (1.96 mL, 26.6 mmol) and4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J.Org. Chem. 2011, 76, 2227-2239) (4.0 g, 10.6 mmol): ¹H NMR (400 MHz,CDCl₃) δ ppm 1.02-1.07 (m, 2H), 1.33-1.37 (m, 2H), 2.98 (s, 2H), 7.35(d, 1H), 7.51 (dd, 1H), 8.02 (d, 1H); MS (CI) m/z 362 [M+H]^(|).

Intermediate 52 6′-Bromospiro[cyclopropane-1,2′-inden]-1′(3′H)-one

A dried flask was charged with1-(4-bromo-2-iodobenzyl)cyclopropanecarbonitrile (Intermediate 51, 3.29g, 9.09 mmol) and dry THF (30 mL) was added under argon atmosphere. Theresulting mixture was cooled to −78° C. and n-BuLi (2.5 M in hexanes,7.27 mL, 18.2 mmol) was added dropwise. The solution was allowed toreach r.t. The reaction was quenched with MeOH (2 mL) and HCl (1M, 5mL). The mixture was extracted with EtOAc. The water phase was basifiedwith sat NaHCO₃ and extracted with EtOAc twice. The organic phases werecombined, dried over MgSO₄, filtered and concentrated in vacuo. HCl (1M, 4 mL) and DCM (5 mL) were added and the organic phase was collected.This was repeated twice. The water phase was basified with sat NaHCO₃and extracted with DCM. The combined organic phases were dried through aphase separator and evaporated to dryness to give the title compound(1.1 g, 51% yield): MS (CI) m/z 237 [M+H]⁺.

Intermediate 53 1-Bromo-3-fluoro-5-(methoxymethyl)benzene

NaH (60% dispersion in mineral oil, 245 mg, 6.12 mmol) was added to asolution of (3-bromo-5-fluorophenyl)methanol (1.195 g, 5.83 mmol) in2-Me THF (20 mL). After gas evolution had ceased, MeI (0.455 mL, 7.29mmol) was added and the resulting mixture was stirred at r.t. for 16 h.Another portion of NaH (50 mg, 2.1 mmol) and Met (0.10 mL, 1.6 mmol)were added and the mixture was heated to 60° C. for 2 h. The cooledmixture was diluted with EtOAc, washed with water, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyon silica (gradient of 0-15% EtOAc in heptane) to give 0.810 g (63%yield) of the title compound: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.30 (s,3H), 4.38-4.46 (m, 2H), 7.18 (m, 1H), 7.37 (s, 1H), 7.44-7.50 (m, 1H);MS (EI) m/z 218 M^(|).

Intermediate 54 3-Bromo-5-((2,2,2-trifluoroethoxy)methyl)pyridine

2,2,2-Trifluoroethanol (0.434 g, 4.34 mmol) was added to a suspension ofNaH (0.198 g, 4.96 mmol) in THF (10 mL). When gas evolution had ceased,a solution of (5-bromopyridin-3-yl)methyl methanesulfonate (seeWO2007/076247; 1.10 g, 4.13 mmol) in DMF was added. The resultingmixture was stirred for 2 h at r.t. and then the volatile solvent wasevaporated. The remaining solution was diluted with water and extractedwith EtOAc (3×30 mL). The combined extracts were dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography on silicausing gradient elution with EtOAc in heptane to give 227 mg of the titlecompound (20% yield). ¹H NMR (500 MHz, CDCl₃) δ ppm 3.92 (q, 2H), 4.70(s, 2H), 7.87 (m, 1H), 8.50 (m, 1H), 8.66 (d, 1H); MS (EI) m/z 269 M⁺.

Intermediate 553-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzonitrile

3-bromo-5-(trifluoromethyl)benzonitrile (1.25 mL, 5.00 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.54 g,10.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II)chloride (288 mg, 0.35 mmol), and potassium acetate (1.47 g, 15.0 mmol)were mixed in dioxane (15 mL) in a round-bottomed flask. The atmospherewas exchanged for argon, and the mixture was heated to 110° C. for 1 h.The reaction mixture was cooled to r.t., filtered through diatomaceousearth, and the filter cake was washed with EtOAc. The filtrate solutionwas washed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography using heptane/EtOAc (70/30)as eluent to give the title compound (495 mg, 33% yield): ¹H NMR (400MHz, CDCl₃) δ ppm 1.37 (s, 12H), 7.98 (m, 1H), 8.26 (s, 2H); MS (ES+)m/z 297 [M+H]⁺.

Intermediate 563-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (643 mg,2.53 mmol), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (50.4 mg,0.08 mmol), and 4,4′-di-tert-butyl-2,2′-dipyridyl (82 mg, 0.30 mmol)were mixed. The atmosphere was exchanged for argon. Hexane (5 mL) wasadded, while the argon atmosphere was maintained. The mixture wasstirred for 5 min at r.t. A solution of 3-(difluoromethyl)benzonitrile(776 mg, 5.07 mmol) in hexane (5 mL) was added, and the mixture wasstirred at r.t. for 16 h. The reaction mixture was diluted with EtOAc,and washed with brine. The organic layer was dried over MgSO₄, filtered,concentrated in vacuo, and purified by flash chromatography usingheptane/EtOAc (85/15) as eluent to give 192 mg (13% yield) of the titlecompound: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (s, 12H), 6.68 (s, 1H)7.86-7.91 (m, 1H) 8.14 (s, 1H) 8.18-8.22 (m, 1H); MS (ES+) m/z 279[M+H]⁺.

Intermediate 573-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A suspension of 5-bromo-3-chloro-2-fluorobenzonitrile (0.959 g, 4.09mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.08g, 8.18 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)chloride (0.234 g, 0.29 mmol), and potassium acetate (1.20 g, 12.3 mmol)in dioxane (15 mL), was placed in a microwave vial. The mixture wasdegassed with a stream of argon for a couple of min, and the reactionmixture was then heated to 110° C. for 1 h in a microwave reactor. Thereaction mixture was cooled to r.t., filtered through diatomaceousearth, and extracted with EtOAc. The organic phase was washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash chromatography using heptane/EtOAc (70/30) as eluentto give the title compound (1.22 g, quantitative yield): GC MS (EI) m/z282 M⁺.

Intermediate 58 3-Bromo-5-ethylbenzonitrile

A mixture of 1,3-dibromo-5-ethylbenzene (2.7 g, 10.2 mmol), coppercyanide (0.916 g, 10.2 mmol), pyridine (1.65 mL, 20.5 mmol) in DMF (15mL) was heated at 150° C. for 3 h. After cooling to r.t., the mixturewas poured into a solution of H₂O (30 mL) and ammonia (25% aq. Solution,20 mL) and extracted with EtOAc. The combined organic layer was dried(MgSO₄), filtered and concentrated in vacuo. The product was purifiedusing flash chromatography on silica gel, gradient elution of 0-60%EtOAc in n-heptane. GCMS (CI) m/z 210 [M+1]⁺.

Intermediate 59 3-Bromo-5-(methoxymethyl)benzonitrile

MeOH (0.088 mL, 2.18 mmol) was added to a slurry of NaH (45 mg, 1.13mmol) in DMF (2 mL). When gas evolution ceased, a solution of3-bromo-5-(bromomethyl)benzonitrile (see WO2009/100169; 240 mg, 0.87mmol) in DMF (1 mL) was added. The reaction was quenched by adding aq.sat NH₄Cl solution. The mixture was partitioned between toluene (5 mL)and water (3 mL). The toluene layer was collected, washed with water,dried over Na₂SO₄, and concentrated in vacuo. The crude product wasdried at reduced pressure and used in the next step: GCMS (CI) m/z 226[M+H]⁺.

Intermediate 606′-Bromo-4-hydroxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

Methylmagnesium chloride (3 M in THF, 3.41 mL, 10.2 mmol) was added, at−15° C., and under Ar, to a solution of6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 5Method A Step 1, 3 g, 10.2 mmol) in THF (4 mL). The reaction was allowedto attain r.t. The mixture was cooled to −15° C., methylmagnesiumchloride (3 M in THF, 3.41 mL, 10.2 mmol) was added and the mixture wasstirred for 1 h at r.t. The reaction was quenched with aq. sat. NH₄Clsolution, and then extracted with DCM. The organic layer was dried overNa₂SO₄ and concentrated in vacuo. The isomeric products were separatedusing a SFC Berger Multigram II System equipped with a Chiralpak AD-Hcolumn (20*250 mm; 5 μm) and a mobile phase consisting of 40% MeOH (with0.1% DEA) and 60% CO₂ at a flow rate of 50 mL/min to give: Isomer 1:(1r,4r)-6′-Bromo-4-hydroxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one,(114 mg, 11% yield) with retention time 3.9 min:

¹H NMR (500 MHz, CDCl₃) δ ppm 1.17 (s, 3H), 1.48 (m, 4H), 1.60 (m, 4H),2.98 (s, 2H), 4.39 (s, 1H), 7.55 (d, 1H), 7.75 (d, 1H), 7.85 (dd, 1H);MS (ES−) m/z 307 [M−H]⁻, and Isomer 2:(1s,4s)-6′-Bromo-4-hydroxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one,(164 mg, 16% yield) with retention time 9.4 min:

¹H NMR (500 MHz, CDCl₃) δ ppm 1.10 (d, 2H), 1.14 (s, 3H), 1.43 (td, 2H),1.56 (d, 2H), 1.95 (td, 2H), 2.97 (s, 2H), 4.11 (s, 1H), 7.53 (d, 1H),7.76 (d, 1H), 7.85 (dd, 1H); MS (ES−) m/z 307 [M−H]⁻.

Intermediate 61(1r,4r)-6′-Bromo-4-methoxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

(1r,4r)-6′-bromo-4-hydroxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 60, Isomer 1, 0.114 g, 0.37 mmol) and methyl iodide (0.046mL, 0.74 mmol) were dissolved in THF (5 mL). Potassium tert-pentoxide(1.7 M in toluene, 0.282 mL, 0.48 mmol) was added dropwise, and themixture was stirred at 30 min. Potassium tert-pentoxide (1.7 M intoluene, 0.217 mL, 0.37 mmol) was added and the mixture was stirred for15 min. A mixture of water (10 mL) and EtOAc (10 mL) was added and theresulting mixture was stirred for 10 min. The organic phase wascollected, dried over Na₂SO₄ and concentrated in vacuo to give the titlecompound (119 mg, 87% yield): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.19 (s,3H), 1.48 (br. s., 4H), 1.53 (m, 4H), 1.66 (m, 2H), 1.83 (m, 2H), 2.86(s, 2H), 3.17 (s, 3H), 7.23 (d, 1H), 7.59 (m, 1H), 7.77 (m, 1H); MS(ES+) m/z 323 [M+H]⁺.

Intermediate 62 6-(3-Fluoropropoxy)-2,3-dihydro-1H-inden-1-one

To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20 mmol)in THF (140 mL) were 3-fluoropropan-1-ol (1.67 mL, 22.3 mmol),triphenylphosphine (7.97 g, 30.4 mmol) and diisopropyl azodicarboxylate(5.98 mL, 30.4 mmol) added. The mixture was stirred at r.t. for twodays. More 3-fluoropropanol (0.5 mL) was added and the mixture washeated to 45° C. After 2 h the mixture was concentrated, and the crudeproduct was purified by flash chromatography using 0-20% EtOAc inheptane as eluent, affording 3.42 g (81% yield) of the title compound:¹H NMR (500 MHz, CDCl₃) δ 2.12-2.26 (m, 2H), 2.68-2.76 (m, 2H),3.04-3.12 (m, 2H), 4.14 (t, 2H), 4.61 (t, 1H), 4.70 (t, 1H), 7.17-7.22(m, 2H), 7.38 (d, 1H); MS (EI) m/z 208 M⁺.

Intermediate 636′-(3-Fluoropropoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

A mixture of 6-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-one(Intermediate 62, 3.42 g, 16.4 mmol) and methyl acrylate (3.26 mL, 36.1mmol) in 2-Me THF (15 mL) was cooled to 0° C. Potassium tert-butoxide(2.21 g, 19.71 mmol) was added in portions. After stirring for 1 h atr.t., water (22.5 mL) and KOH (0.921 g, 16.4 mmol) were added and themixture was heated at reflux for 4.5 h. The mixture was allowed to coolto r.t. and brine was added. The layers were separated and the aqueouslayer was extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo to yield 3.14 g (66%yield) of the title compound which was used in the next step withoutfurther purification: ¹H NMR (400 MHz, CDCl₃) δ 1.82-1.91 (m, 2H),2.13-2.27 (m, 4H), 2.41-2.52 (m, 2H), 2.70 (dt, 2H), 3.16 (s, 2H),4.11-4.17 (m, 2H), 4.60 (t, 1H), 4.72 (t, 1H), 7.21-7.27 (m, 2H), 7.39(dd, 1H); MS (ES+) m/z 291 [M+H]⁺.

Intermediate 646′-(3-Fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

6′-(3-Fluoropropoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione(Intermediate 63, 3.14 g, 10.8 mmol) were dissolved in tetrahydrofuran(50 mL) and MeOH (4.38 mL, 108 mmol). Borane-trimethylamine complex(1.74 g, 23.8 mmol) was added and the resulting mixture was stirredovernight. Citric acid monohydrate (31.8 g, 151 mmol) was added all atonce and was followed by dropwise addition of water (3.90 mL, 216 mmol).The mixture was stirred for 3 h before being diluted with water andextracted with EtOAc (×2). The combined organic phases was dried overMgSO₄ and concentrated in vacuo. The product was purified using silicagel flash chromatography using a gradient of MeOH (0-10%) in DCM to give1.94 (61% yield) of the title compound which was used in the next stepwithout further purification: MS (ES+) m/z 307 [M+H]⁺.

Intermediate 656′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

6′-(3-Fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 64, 1.94 g, 6.64 mmol) was dissolved in tetrahydrofuran(35 mL) under argon and cooled to 0° C. Potassium tert-butoxide (2.23 g,19.9 mmol) was added portion wise and the mixture was stirred at 0° C.for 15 min. Methyl iodide (0.83 mL, 13.3 mmol) was added. The coolingbath was removed, and the mixture was stirred at r.t. overnight. Water(200 mL) was added and the resulting solution was partitioned betweenadditional water (200 mL) and EtOAc (400 mL). The organic phases wasdried over MgSO₄ and concentrated in vacuo. The product was isolatedusing flash chromatography using a gradient of EtOAc (0-50%) in heptaneto give 0.611 g (30% yield) of the title compound: MS (ES+) m/z 307[M+H]⁺.

Intermediate 66 6-Isobutoxy-2,3-dihydro-1H-inden-1-one

To a mixture of 6-hydroxy-2,3-dihydro-1H-inden-1-one (5.0 g, 33.8 mmol)in DMF (170 mL) was added K₂CO₃ (9.33 g, 67.5 mmol) and1-bromo-2-methylpropane (5.50 mL, 50.6 mmol). The resulting orangemixture was stirred at r.t. overnight and was then heated to 60° C. for2 days. The mixture was cooled to r.t., water was added and the mixturewas extracted with EtOAc to (×4). The combined organic layers were driedover MgSO₄ and concentrated in vacuo. Purification by flashchromatography using 0-20% EtOAc in heptane as eluent afforded 4.98 g(72% yield) of the title compound: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.03(d, 6H), 2.10 (dt, 1H), 2.69-2.75 (m, 2H), 3.04-3.11 (m, 2H), 3.75 (d,2H), 7.17-7.22 (m, 2H), 7.37 (d, 1H); MS (ES+) m/z 205 [M+H]⁺.

Intermediate 676′-Isobutoxyspiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

The title compound (3.02 g, 72% yield) was prepared using the methoddescribed for Intermediate 63 starting from6-isobutoxy-2,3-dihydro-1H-inden-1-one (Intermediate 66, 3.0 g, 14.7mmol) and methyl acrylate (2.92 mL, 32.3 mmol): ¹H NMR (400 MHz, CDCl₃)δ ppm 1.04 (m, 8H) 1.86 (m, 2H) 2.11 (dt, 1H) 2.21 (m, 2H) 2.47 (m, 3H)2.70 (m, 2H) 3.15 (s, 2H) 3.76 (m, 3H) 7.20 (m, 1H) 7.25 (m, 1H) 7.38(d, 1H); MS (ES+) m/z 287 [M+H]⁺.

Intermediate 68(1r,4r)-4-Hydroxy-6′-isobutoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

The title compound (1.20 g, 40% yield, containing 5% of another isomer)was prepared using the method described for6′-(3-Fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 64) starting from6′-isobutoxyspiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate67, 3.02 g, 10.6 mmol) and borane-trimethylamine complex (1.69 g, 23.2mmol). The product was purified by flash chromatography using 0-100%EtOAc in heptane as eluent: ¹H NMR (400 MHz, CDCl₃) δ 1.03 (d, J=6.82Hz, 7H), 1.38-1.52 (m, 5H), 1.76-1.87 (m, 2H), 2.02-2.16 (m, 4H), 2.97(s, 2H), 3.70-3.82 (m, 4H), 7.17 (d, J=2.53 Hz, 1H), 7.19-7.24 (m, 1H),7.34 (dd, J=8.34, 0.51 Hz, 1H); MS (ES+) m/z 289 [M+H]⁺.

Intermediate 69(1r,4r)-6′-Isobutoxy-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

(1r,4r)-4-Hydroxy-6′-isobutoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 68, 1.2 g, 4.16 mmol) was dissolved in 2-Me THF (12 mL)under an inert atmosphere, and the solution was cooled to 0° C. Methyliodide (0.338 mL, 5.41 mmol) was added followed by portionwise additionof potassium tert-butoxide (0.654 g, 5.83 mmol). The resulting mixturewas stirred at 35° C. for 1 h. Potassium tert-butoxide (0.233 g, 2.08mmol) was added and stirring continued. After another 30 min, a newportion of potassium tert-butoxide (0.070 g, 0.62 mmol) was added andstirring continued. After a total of 4 h, full conversion was obtainedand water (6 mL) and brine (3 mL) were added. The phases were separatedand the organic layer was dried over Na₂SO₄ and concentrated to yield1.23 g (98% yield) of the title compound: ¹H NMR (400 MHz, CDCl₃) δ ppm1.03 (d, 6H) 1.38 (m, 2H) 1.50 (dt, 2H) 1.78 (m, 2H) 2.09 (m, 1H) 2.15(m, 2H) 2.96 (s, 2H) 3.27 (m, 1H) 3.41 (s, 3H) 3.75 (d, 2H) 7.17 (d, 1H)7.21 (m, 1H) 7.34 (dd, 1H). MS (ES+) m/z 303 [M+H]⁺.

Intermediate 70 3-Bromo-5-[(²H₃)prop-1-yn-1-yl]pyridine

n-BuLi (2.5 M in hexanes, 0.44 mL, 1.10 mmol) was added dropwise, underAr and at 0° C., to a solution of 3-bromo-5-ethynylpyridine (seeWO2005/094822, 200 mg, 1.10 mmol) in THF (2 mL). The mixture was stirredfor 1 h. Iodomethane-d3 (0.56 mL, 1.32 mmol) was added at 0° C. and thereaction was stirred at r.t. for 1 h. The reaction was quenched withammonium chloride solution (aq sat, 2 mL) and extracted with DCM (15mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo.The product was purified by flash chromatography with gradient elutionof 0-30% EtOAc in n-heptane to yield the title compound (77 mg, 35%yield): ¹H NMR (500 MHz, CDCl₃) δ ppm 7.84 (t, 1H), 8.53 (d, 1H), 8.56(d, 1H); MS (ES+) m/z 199 [M+H]⁺.

Intermediate 716″-Bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-one

Ethane-1,2-diol (0.968 mL, 17.4 mmol),6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 5Method A Step 1, 5.09 g, 17.4 mmol) and p-toluenesulfonic acidmonohydrate (0.165 g, 0.87 mmol) in toluene (100 mL), were heated toreflux overnight. The mixture was cooled to r.t. before transferred to aseparation funnel and washed with NaHCO₃ (sat aq). The aqueous phase wasextracted with EtOAc. The combined organic phases were washed withbrine. The formed solid was filtered off and the filtrate concentrated.The filtrate residue was dissolved in EtOAc and washed with water. Moresolid was formed that was collected by filtration. This process wasrepeated three more times until no more solid was formed. The combinedsolids were dried overnight under vacuum to yield 3.76 g of the titlecompound. The remaining organic phase was concentrated to yield 1.9 g ofthe title compound. Combination of the solids gave the title compound(5.66 g, 97% yield): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.50 (dt, 2H)1.66-1.74 (m, 2H) 1.92 (dt, 2H) 2.06 (td, 2H) 3.01 (s, 2H) 3.97-4.03 (m,4H) 7.34 (d, 1H) 7.70 (dd, 1H) 7.89 (d, 1H); MS (ES+) m/z 337 [M+H]^(|).

Intermediate 72 6′-Bromo-4-[(²H₃)methyloxy]spiro[cyclohexane-1,2′-inden]-1′(3′H)-one

6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Step 2, 3 g, 10.2 mmol) (64:36 ratio of isomers (1r,4r)and (1s,4s)) was dissolved in 2-Me THF (30 mL) under an inert atmosphereand the solution was cooled to 0° C. Iodomethane-d3 (0.633 mL, 10.1mmol) was added followed by portionwise addition of potassiumtert-butoxide (1.60 g, 14.2 mmol). The resulting mixture was stirred atr.t. for 1 h. Potassium tert-butoxide (0.456 g, 4.07 mmol) was added andstirring continued. After another 30 min, potassium tert-butoxide (0.342g, 3.05 mmol) was added and stirring continued. After a total of 4 h,water and brine were added. The phases were separated and the organiclayer was extracted with EtOAc. The combined organic layers were driedover MgSO₄ and concentrated. Purification by flash chromatography using0-15% EtOAc in heptane as eluent afforded 1.66 g (52% yield) of thetitle compound as a mixture of isomers (1r,4r) major and (1s,4s) minor.Major isomer: ¹H NMR (500 MHz, CDCl₃) δ 1.20-1.28 (m, 1H), 1.32-1.43 (m,1H), 1.48-1.64 (m, 3H), 1.77 (td, 1H), 2.00-2.11 (m, 1H), 2.12-2.20 (m,1H), 2.98 (s, 2H), 3.23-3.32 (m, 1H), 7.31-7.38 (m, 1H), 7.66-7.73 (m,1H), 7.87-7.90 (m, 1H); MS (ES+) m/z 312 [M+H]^(|).

Intermediate 73 3-Bromo-5-(difluoromethyl)pyridine

5-Bromonicotinaldehyde (5.0 g, 26.9 mmol) was dissolved in DCM (25 mL).The atmosphere was exchanged to argon, and diethylaminosulfurtrifluoride (4.29 mL, 32.3 mmol) was added. The reaction mixture wasstirred at 21° C. for 2 h. The reaction was quenched with 15 mL satNaHCO₃. The phases were separated, and the organic layer was collected,washed with brine, dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by flash chromatography usingheptane/EtOAc 90/10 as eluent to give the title compound (3.66 g, 65%yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.15 (t, 1H) 8.32 (s, 1H) 8.80(s, 1H) 8.91 (s, 1H); MS (EI) m/z 207 M⁺.

Intermediate 743-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A suspension of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.95 g,35.2 mmol), 3-bromo-5-(difluoromethyl)pyridine (Intermediate 73, 3.67 g,17.6 mmol), potassium acetate (5.19 g, 52.9 mmol) in dioxane (70 mL) wasdegassed with a stream of argon for a couple of min. PdCl₂(dppf) CH₂Cl₂(0.179 g, 0.22 mmol) was added and the mixture was heated at refluxunder N₂ for 4 h. The mixture was allowed to cool and was filtered. Thefilter cake was washed with EtOAc and the filtrate was concentrated invacuo. The residue was purified with flash chromatography on silica gel,gradient elution with EtOAc in n-heptane. The title compound (2.0 g)that still contained some impurities was used as such in the next step:MS (EI) m/z 207 M⁺.

Intermediate 75 1-Bromo-2-chloro-3-(prop-1-ynyl)benzene

To a microwave vial were added 1,3-dibromo-2-chlorobenzene (780 mg, 2.89mmol), trimethyl(prop-1-ynyl)silane (0.645 mL, 4.33 mmol), copper iodide(28 mg, 0.14 mmol), PdCl₂(dppf) CH₂Cl₂ (118 mg, 0.14 mmol),tetrabutylammonium fluoride (1 Min THF, 8.66 mL, 8.66 mmol),diisopropylamine (1.23 mL, 8.66 mmol) and anhydrous DMF (5 mL). The vialwas capped and purged with argon and the mixture was irradiated at 100°C. for 1 h in a microwave reactor. The mixture was diluted with waterand extracted with DCM three times, dried through a phase separator andconcentrated in vacuo. The product was purified by flash chromatography(100% heptanes as eluent) to give 146 mg (22% yield) of the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.13 (s, 3H) 7.24 (t, J=7.88Hz, 1H) 7.53 (dd, J=7.57, 1.26 Hz, 1H) 7.74 (dd, J=8.04, 1.42 Hz, 1H);MS (CI) m/z 231 [M+H]⁺.

Intermediate 76 4-(Trifluoromethyl)cyclohexanecarboxylate

4-(Trifluoromethyl)cyclohexanecarboxylic acid (5.00 g, 25.5 mmol) wasdissolved in toluene (100 mL), and sulfuric acid (0.014 mL, 0.25 mmol)was added. The reaction mixture was reacted under Dean-Stark conditionsfor 16 h. The reaction mixture was cooled to r.t., and diluted withEtOAc. The solution was washed with sat aq. NaHCO₃. The organic layerwas washed with brine, and concentrated in vacuo providing the titlecompound (5.64 g, 99% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (d,1H) 1.19-1.30 (m, 2H) 1.38-1.50 (m, 3H) 1.83 (d, 2H) 2.18 (s, 3H)2.91-3.12 (m, 3H) 3.20 (s, 3H) 6.55 (br. s., 2H) 6.89 (d, 1H) 7.01-7.26(m, 1H) 7.43 (d, 1H) 7.60 (dd, 1H) 8.01 (d, 2H) 8.22 (s, 1H); MS (ES+)m/z 449 [M+H]⁺ and (ES−) m/z 447 [M−H]⁻.

Intermediate 77 Ethyl1-(4-bromo-2-iodobenzyl)-4-(trifluoromethyl)cyclohexanecarboxylate

Ethyl 4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 76, 1.492g, 6.65 mmol) was dissolved in THF (25 mL). The atmosphere was exchangedto argon, and the solution was cooled to −78° C. Lithiumdiisopropylamide (1.8 M in THF/heptane/ethylbenzene) (4.07 mL, 7.32mmol) was added, while the temperature was kept at −78° C. The solutionwas stirred for 30 min at −78° C. 4-Bromo-1-(bromomethyl)-2-iodobenzene(see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239, 2.50g, 6.65 mmol) in THF (25 mL) was added via a syringe. The mixture wasallowed to reach r.t., while stirred for 2 h. Water (10 mL) was added tothe reaction mixture, followed by EtOAc (40 mL). The phases wereseparated. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatography(eluent: heptane/EtOAc 95/5) to give the title compound (2.41 g, 69%yield): ¹H NMR (400 MHz, CDCl₃) δ ppm 1.22-1.27 (m, 3H) 1.29-1.43 (m,4H) 1.82-1.90 (m, 2H) 1.82-1.90 (m, 3H) 1.97 (br. s., 2H) 2.28-2.36 (m,3H) 3.01 (s, 3H) 4.18 (q, 3H) 6.91 (m, 1H) 7.38 (m, 1H) 7.99 (m, 1H); MS(ES+) m/z 520 [M+H]⁺.

Intermediate 786′-Bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one

Ethyl 1-(4-bromo-2-iodobenzyl)-4-(trifluoromethyl)cyclohexanecarboxylate(Intermediate 77, 2.41 g, 4.64 mmol) was dissolved in THF (40 mL). Theatmosphere was exchanged to argon, and the solution was cooled to −78°C. Isopropylmagnesium chloride-lithium chloride (1.3 M in THF) (2.86 mL,3.71 mmol) was added dropwise. The reaction mixture was stirred at −78°C. for 15 min. The reaction mixture left to warm up to r.t., whilestirred for 30 min. The reaction mixture was quenched with sat. NH₄Cl.Brine was added, and the phases were separated. The organic layer waswashed with brine, dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by preparative chromatography (XBridgeC18 (10 μm, 50×250 mm) column with a gradient of 50-100% MeCN) in (95%0.05M NH₄OAc in MilliQ water and 5% MeCN) over 15 min at a flow rate of100 mL/min). The purification provided the title compound (0.849 g, 52%yield): ¹H NMR (400 MHz, CDCl₃) δ ppm 1.51-1.61 (m, 3H) 1.75-1.84 (m,2H) 1.97 (m, 2H) 2.18 (m, 2H) 2.90 (s, 2H) 7.29 (dd, 1H) 7.69 (dd, 1H)7.84 (d, 1H); MS (ES+) 346 [M+H]⁺.

Intermediate 792-Fluoro-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A flask containing 2-fluoro-3-methoxybenzonitrile (302 mg, 2.00 mmol),4,4′-di-tert-butyl-2,2′-dipyridyl (8 mg, 0.03 mmol) andbis(pinacolato)diboron (254 mg, 1.0 mmol) was flushed with argon, andthen charged with hexane (6 mL). The mixture was then stirred at 25° C.overnight. The reaction mixture was diluted with EtOAc and washed withbrine. The organic phase was concentrated and the crude product waspurified on a silica column (0-50% EtOAc/n-heptane) to give the titlecompound (362 mg with 73% purity according to HPLC): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.63-7.55 (m, 2H), 3.93 (s, 3H), 1.31 (s, 12H); MS (EI)m/z 277 M⁺.

Intermediate 806′-Bromo-4-ethoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

6′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one as a 2:1mixture of isomers (Intermediate 5 Step 2, 10.4 g, 34.1 mmol) and ethyliodide (3.6 mL, 44.3 mmol) were dissolved in 2-MeTHF (100 mL) under N₂.KOt-Bu (7.65 g, 68.2 mmol) was added portionwise to the reactionmixture, keeping the internal temperature below 30° C. The solution wasstirred at r.t. overnight. Water (40 mL) and brine (25 mL) were addedand the mixture was further stirred for 5 min. The mixture was dilutedwith brine and 2-Me-THF until two layers formed. The phases wereseparated. Activated charcoal was added to the organic layer which wasthen stirred for 10 min. Diatomaceous earth was added and the mixturewas further stirred for 5 min. The mixture was filtered through a plugof silica gel and diatomaceous earth, which was rinsed withheptane/EtOAc 7:3. The filtrate was concentrated. The filtrationsequence was repeated, affording 4.0 g (36% yield) of the title compound(as a 2:1 mixture of isomers): ¹H NMR (300 MHz, CDCl₃) δ ppm 1.22 (t,3H), 1.32-1.45 (m, 2H), 1.45-1.52 (m, 2H), 1.77 (dt, 2H), 2.07-2.16 (m,2H), 2.98 (s, 2H), 3.30-3.40 (m, 1H), 3.57 (q, 2H), 7.34 (d, 1H), 7.69(dd, 1H), 7.87 (d, 1H).

Intermediate 816′-(3,3,3-Trifluoropropoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione

The title compound (854 mg, 58% yield) was prepared using the methoddescribed for Intermediate 63 starting from6-(3,3,3-trifluoropropoxy)-2,3-dihydro-1H-inden-1-one (Intermediate 47,1.08 g, 4.42 mmol) and methyl acrylate (878 μL, 9.73 mmol): ¹H NMR (500MHz, CDCl₃) δ ppm 1.82-1.92 (m, 2H), 2.17-2.27 (m, 2H), 2.42-2.53 (m,2H), 2.60-2.75 (m, 4H), 3.14-3.20 (m, 2H), 4.22-4.27 (m, 2H), 7.19-7.22(m, 1H), 7.25 (dd, 1H), 7.41 (d, 1H): MS (ES+) m/z 327 [M+H]⁺.

Intermediate 82(1r,4r)-4-Hydroxy-6′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one

The title compound (357 mg, 51% yield, containing 16% of another isomer)was prepared using the method described for Intermediate 64 startingfrom6′-(3,3,3-trifluoropropoxy)spiro-[cyclohexane-1,2′-indene]-1′,4(3′H)-dione(Intermediate 81, 689 mg, 2.11 mmol) and borane-trimethylamine complex(339 mg, 4.65 mmol). The product was purified by flash chromatographyusing 0-100% EtOAc in heptane as eluent: ¹H NMR (500 MHz, CDCl₃) δ ppm1.40-1.52 (m, 4H), 1.82 (td, 2H), 2.03-2.13 (m, 2H), 2.65 (qt, 2H), 2.99(s, 2H), 3.73-3.82 (m, 1H), 4.23 (t, 2H), 7.16-7.20 (m, 1H), 7.22 (dd,1H), 7.38 (d, 1H); MS (ES+) m/z 329 [M+H]⁺.

Intermediate 83((1r,4r)-4-Methoxy-6′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one

(1r,4r)-4-Hydroxy-6′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 82, 357 mg, 1.09 mmol) was dissolved in 2-Me THF (7 mL)under an inert atmosphere, and the solution was cooled to 0° C. Methyliodide (88 μL, 1.41 mmol) was added followed by portionwise addition ofpotassium tert-butoxide (171 mg, 1.52 mmol). The resulting mixture wasstirred at r.t. for 1 h. Some alcohol remained so more potassiumtert-butoxide (61 mg, 0.54 mmol) was added and stirring continued. After30 min, water and brine were added. The phases were separated and theorganic layer was dried over MgSO₄ and concentrated. Purification byflash chromatography using 0-25% EtOAc in heptane as eluent afforded 201mg (54% yield) of the title compound (containing 11% of another isomer):¹H NMR (500 MHz, CDCl₃) δ 1.32-1.44 (m, 2H), 1.51 (d, 2H), 1.78 (td,2H), 2.12-2.21 (m, 2H), 2.59-2.70 (m, 2H), 2.97 (s, 2H), 3.24-3.32 (m,1H), 3.41 (s, 3H), 4.23 (t, 2H), 7.16-7.23 (m, 2H), 7.37 (d, 1H); MS(ES+) m/z 343 [M+H]⁺.

Intermediate 84 3-(Bromomethyl)-2-fluorobenzonitrile

NBS (1.729 g, 9.71 mmol) was added to a solution of2-fluoro-3-methylbenzonitrile (1.25 g, 9.25 mmol) in acetonitrile (25mL). The obtained mixture was refluxed, and then benzoic peroxyanhydride(0.045 g, 0.18 mmol) was added. The reaction mixture was refluxedovernight, then cooled to r.t. and water was added. The aqueous phasewas discarded and the organic phase was dried over MgSO₄ andconcentrated. The crude product was purified by flash chromatographyusing a gradient of EtOAc in heptane as eluent to give the titlecompound (1.39 g, 70% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.75 (s,2H) 7.43 (t, 1H) 7.93 (t, 2H); MS (EI) m/z 213 M⁺.

Intermediate 85 2-Fluoro-3-(methoxymethyl)benzonitrile

3-(Bromomethyl)-2-fluorobenzonitrile (Intermediate 84, 1.39 g, 6.49mmol) was dissolved in MeOH (10 mL) and sodium methoxide (1.238 mL, 6.49mmol) was added. The mixture was stirred at r.t. for 2 h. This mixturewas concentrated and then partitioned between water and EtOAc. Theorganic layer was separated and then concentrated in vacuo. Theresulting residue was purified by flash chromatography usingEtOAc/heptanes as eluent to give the title compound (0.900 g, 84%yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.32 (s, 3H) 4.52 (br. s, 2H)7.42 (t, 1H) 7.77-7.84 (m, 1H) 7.86-7.92 (m, 1H); MS (EI) m/z 166 M⁺.

Intermediate 862-Fluoro-3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.15 g,4.53 mmol), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (45 mg, 0.07mmol), and 4,4′-di-tert-butyl-2,2′-dipyridyl (72.9 mg, 0.27 mmol) wereadded to a reaction flask. The atmosphere was exchanged to argon. Hexane(10 mL) was added, while the argon atmosphere was maintained. Themixture was stirred for 5 min at r.t. The color of the reaction mixtureturned red. A solution of 2-fluoro-3-(methoxymethyl)benzonitrile(Intermediate 85, 748 mg, 4.53 mmol) in hexane (10 mL) was added, andthe mixture was refluxed for 2 h. The reaction mixture was diluted withEtOAc and washed with brine. The organic layer was collected, dried overMgSO₄, filtered and concentrated. The residue was purified by flashchromatography using EtOAc/heptane eluent system to give 254 mg (19%yield) of the title compound: MS (EI) m/z 291 M⁺.

Intermediate 87 Methyl 4-(hydroxymethyl)cyclohexanecarboxylate

To a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (5.44 g,29.2 mmol) in dry THF at −78° C., was added borane-methyl sulfidecomplex (19.0 mL, 38.0 mmol) dropwise over 20 min. The mixture wasstirred for 3 h and was then allowed to slowly attain r.t. The reactionwas quenched with water (20 mL) and the mixture was extracted withEtOAc. The organic phase was washed once with brine, dried over MgSO₄and concentrated in vacuo to give the title compound (4.80 g, 95% yield)as a mixture of two diastereomers: MS (EI) m/z 172 M⁺.

Intermediate 88 Methyl 4-formylcyclohexanecarboxylate

To a solution of methyl 4-(hydroxymethyl)cyclohexanecarboxylate(Intermediate 87, 4.08 g, 23.7 mmol) in DCM was added NaHCO₃ (9.95 g,118 mmol), followed by Dess-Martin Periodinane (12.1 g, 28.4 mmol). Themixture was stirred at r.t. for 2.5 h. Et₂O (60 mL) was added followedby an aq. solution of NaHCO₃ (1 M, 60 mL) and a 20% aq. solution ofsodium thiosulfate (40 mL). The resulting mixture was stirred overnight.The phases were separated and the aqueous phase was extracted with Et₂O.The organic phase was washed with brine and dried over MgSO₄, filteredand concentrated in vacuo to yield the title compound (4.0 g, 99%yield): MS (EI) m/z 170 M⁺.

Intermediate 89 Methyl 4-(difluoromethyl)cyclohexanecarboxylate

Methyl 4-formylcyclohexanecarboxylate (Intermediate 88, 4.0 g, 23.5mmol) was dissolved in dry DCM (80 mL). Bis(2-methoxyethyl)amino-sulfurtri fluoride (3.42 mL, 25.9 mmol) was added dropwise over 20 min. Thereaction mixture was stirred for 1.5 h. Water (40 mL) was added dropwiseand the reaction mixture was stirred for 2 min. The organic phase wasseparated from the water phase with a phase separator and evaporated invacuo to give the title compound (4.28 g, 95% yield): MS (CI) m/z 193[M+H]⁺.

Intermediate 90 Methyl1-(4-bromo-2-iodobenzyl)-4-(difluoromethyl)cyclohexanecarboxylate

Methyl 4-(difluoromethyl)cyclohexanecarboxylate (Intermediate 89, 2.46g, 12.8 mmol) was dissolved in THF (25 mL). The atmosphere was exchangedto N₂ (g), and the solution was cooled to −78° C. Lithiumdiisopropylamide (1.8M in THF/heptane/ethylbenzene) (8.51 mL, 15.3 mmol)was added, while the temperature was kept at −78° C. The solution wasstirred for 60 min at −78° C. A solution of4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J.Org. Chem. 2011, 76, 2227-2239, 4.8 g, 12.8 mmol) in THF (5.0 mL) wasadded via syringe. The reaction was removed from the cooling bath, andallowed to reach r.t., while stirred for 2.5 h. Water (30 mL) was added,followed by DCM (30 mL). The organic layer was collected and dried overMgSO₄, filtered and evaporated in vacuo. The residue was purified byflash chromatography, (0-100% EtOAc in heptanes, 220 g SiO₂) to give thetitle compound (3.29 g, 53% yield): ¹H NMR (500 MHz, CDCl₃) δ ppm1.11-1.20 (m, 2H), 1.39 (td, 2H), 1.67-1.80 (m, 3H), 2.30 (d, 2H), 3.01(s, 2H), 3.70 (s, 3H), 5.49 (d, 1H), 6.89 (d, 1H), 7.38 (dd, 1H), 7.99(d, 1H), MS (CI) m/z 487 [M+H]^(|).

Intermediate 916′-Bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one

Methyl 1-(4-bromo-2-iodobenzyl)-4-(difluoromethyl)cyclohexanecarboxylate(Intermediate 90, 2.3 g, 4.72 mmol) was dissolved in THF (30 mL). Theatmosphere was exchanged to N₂ (g), and the solution was cooled to −20°C. Isopropylmagnesium chloride-lithium chloride (1.3M in THF, 4.00 mL,5.19 mmol) was added dropwise over one h. The reaction mixture wasstirred at −20° C. for 40 min. The reaction mixture was removed from thecooling bath, and left to warm up to r.t., while stirred for 1.5 h. Thereaction was stirred at r.t. overnight and then heated at 40° C. for 3h. The reaction was cooled to r.t. and quenched with sat. NH₄Cl. Theresulting mixture was stirred overnight. The organic layer was collectedand dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography (0-10% EtOAc in heptane) followed bypreparative chromatography to give the title compound (0.562 g, 24%yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.46-1.65 (m, 4H), 1.75-1.96 (m,5H), 2.93 (s, 2H), 6.00 (dt, 1H), 7.51 (d, 1H), 7.73 (d, 1H), 7.83 (dd,1H).

Example 16-(3,5-Dichlorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (73 mg, 0.25mmol, Intermediate 4), 3,5-dichlorophenylboronic acid (95 mg, 0.50 mmol)and K₂CO₃ (83 mg, 0.60 mmol) were mixed in dioxane (2 mL) and degassedby passing nitrogen through for 5 min. Then(1,1′-bis(diphenyl-phosphino)ferrocene)-dichloropalladium(II) (10 mg,0.01 mmol) was added and the mixture was heated in a sealed vial at 100°C. overnight.(1,1′-Bis(diphenylphosphino)ferrocene)-dichloro-palladium(II) (10 mg,0.01 mmol) was added and heating continued in a microwave oven at 130°C. for 2×1 h. Purification by preparative HPLC gave the title compound(13 mg, 14% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm 2.04-2.30 (m, 2H),2.38 (s, 3H), 4.50-4.69 (m, 2H), 4.88 (br s, 2H), 6.69 (s, 1H), 6.98 (d,1H), 7.22-7.35 (m, 4H); MS (ES+) m/z 360 [M+H]⁺.

Example 26-(5-Chloropyridin-3-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (60 mg, 0.20mmol, Intermediate 4), 5-chloropyridin-3-ylboronic acid (62 mg, 0.40mmol) and 2M K₂CO₃ (aq, 0.20 mL, 0.41 mmol) were mixed in dioxane (5 mL)and degassed by passing nitrogen through for 5 min. Then(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (8 mg, 10μmol) was added and the mixture was heated in a microwave oven at 130°C. for 1 h. Purification by preparative chromatography HPLC gave thetitle compound (42 mg, 63% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm 2.17(m, 2H), 2.37 (s, 3H), 4.59 (m, 2H), 5.04 (br s, 2H), 6.73 (d, 1H), 7.01(d, 1H), 7.34 (dd, 1H), 7.70 (m, 1H), 8.45 (m, 1H), 8.55 (m, 1H); MS(ES+) m/z 327 [M+H]⁺.

Example 36-(3,5-Difluorophenyl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (Intermediate 4,0.10 g, 0.34 mmol), 3,5-difluorophenylboronic acid (0.11 g, 0.68 mmol)and 2M K₂CO₃ (aq., 0.34 mL, 0.69 mmol) were mixed in dioxane (3 mL) anddegassed by passing through nitrogen for 5 min. Then(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (14 mg, 20μmol) was added and the mixture was heated in a microwave oven at 130°C. for 1 h. Purification by preparative chromatography gave the titlecompound (17 mg, 15% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm 2.25 (m, 2H),2.41 (s, 3H), 4.57 (m, 2H), 6.66-6.86 (m, 2H), 6.89-7.05 (m, 3H), 7.38(d, 1H), 8.1-9.0 (br m, 2H); MS (ES+) m/z 328 [M+H]⁺.

Examples 4-12

To a mixture of 6-bromo-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine(Intermediate 4, 0.20 mmol, 1.0 eq) and the corresponding boronic acidR²—B(OH)₂ (0.40 mmol, 2.0 eq) in a mixture of 1,4-dioxane, EtOH andwater (2 mL, v:v:v=4:1:1) was added Pd₂(dba)₃ (0.02 mmol, 0.1 eq) andX-Phos (0.02 mmol, 0.1 eq) followed by Na₂CO₃ (0.40 mmol, 2.0 eq) undernitrogen. The reaction mixture was stirred at 90° C. overnight. Thecrude product was purified by preparative TLC to afford the respectivecompound in Table 1.

TABLE 1 LC MS (ES+) Yield Yield observed ion Example R² Name (mg) (%)m/z [M + H]⁺ 4

6-(3,5- Dimethylphenyl)-5′- methylspiro[chroman- 4,2′-imidazol]-4′-amine20 32 320.1 5

6-(2,5- Dimethoxyphenyl)-5′- methylspiro[chroman-4,2′-imidazol]-4′-amine 25 36 352.1 6

6-(2,3- Difluorophenyl)-5′- methylspiro[chroman- 4,2′-imidazol]-4′-amine17 26 328.1 7

6-(2,5- Dimethylphenyl)-5′- methylspiro[chroman- 4,2′-imidazol]-4′-amine15 23 320.1 8

6-(5-Fluoro-2- methoxyphenyl)-5′- methylspiro[chroman-4,2′-imidazol]-4′-amine 23 35 340.1 9

6-(2-Fluoro-3- methoxyphenyl)-5′- methylspiro[chroman-4,2′-imidazol]-4′-amine 24 35 340.1 10

6-(2-Methoxy-5- methylphenyl)-5′- methylspiro[chroman-4,2′-imidazol]-4′-amine 29 43 336.1 11

6-(2-Fluoro-5- methylphenyl)-5′- methylspiro[chroman-4,2′-imidazol]-4′-amine 22 34 324.1 12

6-(2-Fluoro-5- methoxyphenyl)-5′- methylspiro[chroman-4,2′-imidazol]-4′-amine 20 29 340.1

Example 13aN-(4′-Amino-5′-methylspiro[chroman-4,2′-imidazole]-6-yl)-5-chloropicolinamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg,0.30 mmol) was added to a suspension of 5-chloropyridine-2-carboxylicacid (37 mg, 0.23 mmol) in DCM (1.5 mL). The obtained solution wasstirred for 10 min and added dropwise over 2 min to an ice-cooledsolution of 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine(Intermediate 30, 54 mg, 0.23 mmol) and 2 M HCl (0.117 mL, 0.23 mmol) inDMF (1.5 mL). The mixture was stirred at 0° C. for 5 min. Volatiles wereremoved in vacuo, and the residue was purified by preparativechromatography. Fractions containing the product were combined, and theorganic solvent was removed in vacuo. The aqueous residue was alkalizedwith (sat) NaHCO₃ and then extracted twice with EtOAc. The combinedorganic phases were dried (Na₂SO₄) and evaporated to give a productwhich was purified by flash chromatography (4 g, gradient elution(EtOAc/MeOH/conc. NH₃) in heptane) affording the title compound (27 mg,31% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92 (br. s., 2H), 2.23 (s,3H), 4.23-4.54 (m, 2H), 6.56 (br. s., 2H), 6.80 (d, 1H), 7.05 (br. s.,1H), 7.54-7.72 (m, 1H), 8.04-8.12 (m, 1H), 8.13-8.23 (m, 1H), 8.72 (br.s., 1H), 10.41 (s, 1H); HPLC, MS (APCI) m/z 370 [M+H]⁺.

Example 13cN-(4′-Amino-5′-methylspiro[chroman-4,2′-imidazole]-6-yl)-5-(trifluoromethyl)picolinamide

The title compound (44 mg, 46% yield) was prepared as described forExample 13a starting from 5-(trifluoromethyl)picolinic acid (45 mg, 0.23mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine(Intermediate 30, 54 mg, 0.23 mmol): ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.85-1.98 (m, 2H), 2.24 (s, 3H), 4.30-4.50 (m, 2H), 6.56 (s, 2H), 6.81(d, 1H), 7.02-7.10 (m, 1H), 7.62-7.71 (m, 1H), 8.28 (d, 1H), 8.46 (dd,1H), 9.01-9.10 (m, 1H), 10.57 (s, 1H); MS (APCI⁺) m/z 404 [M+H]⁺.

Example 13dN-(4′-amino-5′-methylspiro[chroman-4,2′-imidazole]-6-yl)-5-(but-2-ynyloxy)picolinamide

The title compound (15 mg, 16% yield) was prepared as described forExample 13a starting from 5-(but-2-ynyloxy)picolinic acid (Intermediate19, 45 mg, 0.24 mmol) and5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30,54.7 mg, 0.24 mmol): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.87 (t, 3H), 2.03(m, 1H), 2.30 (m, 1H), 2.39 (m, 3H), 4.50 (m, 1H), 4.62 (m, 1H), 4.76(m, 2H), 6.92 (d, 1H), 6.98 (m, 1H), 7.41 (dd, 1H), 7.49 (m, 1H), 8.18(d, 1H), 8.28 (d, 1H), 9.61 (s, 1H); MS (ES+) m/z 404 [M+H]⁺.

Example 13eN-(4′-Amino-5′-methylspiro[chroman-4,2′-imidazole]-6-yl)-5-(but-2-ynyloxy)pyrazine-2-carboxamide

The title compound (28 mg, 24% yield) was prepared as described forExample 13a starting from 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid(Intermediate 36, 58 mg, 0.30 mmol) and5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate 30, 63mg, 0.27 mmol). The crude product was purified by flash chromatography(4 g silica, gradient elution of (EtOAc/MeOH/conc. NH₃ (80/20/1) inheptane) followed by preparative chromatography. The to pure fractionswere combined and evaporated. The residual oil was solidified byevaporation with EtOAc and heptanes: ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.85 (t, 3H), 1.88-1.96 (m, 2H), 2.23 (s, 3H), 4.28-4.48 (m, 2H), 5.07(q, 2H), 6.55 (s, 2H), 6.79 (d, 1H), 7.02-7.10 (m, 1H), 7.55-7.64 (m,1H), 8.39 (d, 1H), 8.84 (d, 1H), 10.26 (s, 1H); MS (APCI m/z 405 [M+H]⁺.

Example 13fN-(4′-Amino-5′-methylspiro[chroman-4,2′-imidazole]-6-yl)-5-methylthiophene-2-carboxamide

The title compound (45.5 mg, 57% yield) was prepared as described forExample 13a starting from 5-methylthiophene-2-carboxylic acid (32.1 mg,0.23 mmol) and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine(Intermediate 30, 52 mg, 0.23 mmol): ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.91 (m, 2H), 2.23 (s, 3H), 2.47 (s, 3H), 4.39 (m, 2H), 6.55 (s, 2H),6.73 (d, 1H), 6.78 (d, 1H), 6.86 (dd, 1H), 7.50 (dd, 1H), 7.73 (d, 1H),9.86 (s, 1H); MS (ES+) m/z 355 [M+H]⁺.

Example 13iN-(4′-Amino-5′-methylspiro[chroman-4,2′-imidazole]-6-yl)-3,5-dichloropicolinamide

The title compound (59 mg, 62% yield) was prepared as described forExample 13a starting from 3,5-dichloropicolinic acid (45 mg, 0.23 mmol)and 5′-methylspiro[chroman-4,2′-imidazole]-4′,6-diamine (Intermediate30, 54 mg, 0.23 mmol): ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.82-2.01 (m,2H), 2.22 (s, 3H), 4.29-4.49 (m, 2H), 6.57 (s, 2H), 6.75-6.85 (m, 2H),7.48-7.57 (m, 1H), 8.41 (d, 1H), 8.68 (d, 1H), 10.39 (s, 1H); MS (APCI⁺)m/z 404 [M+H]⁺.

Example 156′-Bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

Step 1:N-((1r,4r)-5′-Bromo-4-hydroxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

Titanium ethoxide (0.733 mL, 3.56 mmol), 2-methyl-2-propanesulfinamide(0.411 g, 3.39 mmol) and(1r,4r)-6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Step 2 Isomer 1) (0.5 g, 1.69 mmol) in dry2-methyl-tetrahydrofuran (7.5 mL) were refluxed for 3 days.2-Methyl-2-propanesulfinamide (0.411 g, 3.39 mmol), titanium ethoxide(0.733 mL, 3.56 mmol) and 2-methyl-tetrahydrofuran (3 mL) were added andthe mixture was refluxed for four more days. The cooled mixture wasadded to a mixture of MeOH (12.5 mL), NaHCO₃ (aq sat) (5 mL) and EtOAc(50 mL). The resulting slurry was stirred for 90 min and was thenfiltered through a mixture of diatomaceous earth and Na₂SO₄ and thenconcentrated in vacuo. Purification by flash chromatography using agradient of CHCl₃/MeOH (40:1-30:1-20:1) gave the title compound (0.398g, 59% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.21-1.78 (m, 15H), 1.83(m, 2H), 2.96-3.01 (m, 2H), 3.44 (m, 1H), 4.63-4.72 (m, 1H), 7.50 (d,1H), 7.73-7.82 (m, 1H), 8.51 (br. s., 1H); MS (ES+) m/z 398 [M+H]⁺.

Step 2:(1r,4r)-6′-Bromo-4-hydroxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

ToN-((1r,4r)-5′-bromo-4-hydroxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 15 Step 1) (2.21 g, 5.55 mmol) in dioxane (10 mL) under N₂ (g)was added HCl (4 M in 1,4-dioxane) (13.87 mL, 55.48 mmol). The mixturewas stirred at r.t for 2 h and was then concentrated. DCM and Et₂O wereadded resulting in the formation of a solid. The solid was filtered offand washed with Et₂O. The solid was dissolved in DCM. NaHCO₃ (sat. aq)was added and the mixture was poured into a phase separator. The organicphase was collected and concentrated. The residue, containing(1r,4r)-6′-bromo-1′-imino-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-ol,and 2-oxopropanethioamide (Intermediate 2, 1.55 g, 15.0 mmol) wasdissolved in dry MeOH (25 mL) and heated at 60° C. under N₂ (g)overnight. A solid formed and was filtered off. The filtrate wasconcentrated. Purification by flash chromatography using a gradient of0-100% EtOAc in n-heptane gave the title compound (1.334 g, 63% yield):¹H NMR (400 MHz, DMSO-d₆) δ 1.05-1.32 (m, 4H), 1.43 (m, 2H), 1.70 m,2H), 2.26 (s, 3H), 2.98 (d, 1H), 3.06 (d, 1H), 3.26 (m, 1H), 4.58 (d,1H), 6.97 (d, 1H), 7.35 (d, 1H), 7.51 (dd, 1H), 12.34 (s, 1H); MS (ES+)m/z 379 [M+H]⁺.

Step 3:(1r,4r)-6′-Bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-hydroxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 15 Step 2, 500 mg, 1.32 mmol) was co-evaporated with dry MeCNtwice after which it was suspended in dry MeCN (19 mL), cuprous iodide(25.1 mg, 0.13 mmol) was added and the resulting mixture was heated at60° C. for 5 min under argon. 2-(fluoro-sulphonyl)difluoroacetic acid(0.217 mL, 1.98 mmol) was added in a stream and the reaction mixture washeated at 60° C. After 1 h more 2-(fluorosulphonyl)difluoroacetic acid(0.217 mL, 1.98 mmol) was added. After heating for another hour, water,Et₂O and EtOAc were added. The phases were separated and the aqueousphase was extracted once with EtOAc. The combined to organic phases weredried (Na₂SO₄), filtered and concentrated. To the residue, containing(1r,4r)-6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione,was added ammonia (7 M in MeOH) (18 mL, 126 mmol) and the mixture wasmicrowaved for 40 min. at 100° C. The mixture was concentrated andre-dissolved in ammonia (7 M in MeOH) (18 mL, 126 mmol) and microwavedagain for 40 min. at 100° C. The mixture was concentrated. Purificationby flash chromatography using a gradient of CHCl₃/MeOH 30:1-20:1 gavethe title compound (411 mg, 76% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.95-1.06 (m, 1H), 1.35-1.54 (m, 5H), 1.79 (m, 2H), 2.17 (s, 3H), 2.93(d, 1H), 3.04 (d, 1H), 3.87 (m, 1H), 6.61 (s, 2H), 6.65 (m, 2H), 7.26(d, 1H), 7.35 (dd, 1H); MS (ES+) m/z 412 [M+H]⁺.

Example 196′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineMethod A Step 1:(N-(5′-Bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide)

6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Method A Step 3, mixture of isomers, 1.14 g, 3.69 mmol),2-methylpropane-2-sulfinamide (0.670 g, 5.53 mmol) and titanium ethoxide(1.519 mL, 7.37 mmol) were dissolved in 2-Me THF (8 mL) and heated toreflux for 26 h. The reaction was left to cool down to r.t. EtOAc (80mL) and NaHCO₃ (sat, 15 mL) was added under stirring. The mixture wasthen standing without stirring for 15 min. The organic phase wascollected by filtration, dried over MgSO₄ and concentrated. Flashchromatography with a gradient of 0-20% EtOAc in n-heptane gave thetitle compound (1.00 g, 66% yield). ¹H NMR (500 MHz, CD₃CN, signals forthe major isomer) S ppm 0.85-0.91 (m, 1H), 1.27 (s, 9H), 1.25-1.86(multiplets, 5H), 2.01-2.10 (m, 2H), 3.02 (br. s, 2H), 3.18-3.26 (m,1H), 3.31 (s, 3H), 7.37 (d, 1H), 7.67 (dd, 1H), 8.59 (br. s., 1H), MS(ES+) m/z 413 [M+H]⁺.

Step 2: 6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

To a solution ofN-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 19 Step 1, mixture of isomers, 2 g, 4.85 mmol) in anhydrous1,4-dioxane (25 mL) was added 4M HCl in 1,4-dioxane (12.12 mL, 48.50mmol). A white precipitate was formed immediately and the resultingcloudy mixture was stirred under a nitrogen atmosphere at r.t. for 90min. Et₂O (30 mL) was added and the solid was filtered off and washedwith Et₂O. The solid was partitioned between DCM (40 mL) and sat. aq.NaHCO₃ (40 mL). The phases were separated and the organic layerconcentrated. The crude title compound (1.41 g) was used directly in thenext step. MS (EI) m/z 307 M⁺.

Step 3:6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example19 Step 2, 1.41 g, 4.57 mmol) and 2-oxopropanethioamide (Intermediate 2,1.42 g, 13.7 mmol) were dissolved in dry MeOH (30 mL) and the resultingsolution was heated at 60° C. under an atmosphere of nitrogen. After 15h the reaction was allowed to cool to r.t. A precipitate had formedwhich was filtered off and dried in vacuo, yielding the title compound(1.16 g, 64% yield) as a mixture of isomers. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.18 (m, 4H), 1.47 (m, 2H), 1.87 (m, 2H), 2.27 (m, 3H), 3.03 (m,3H), 3.20 (s, 3H), 6.98 (d, 1H), 7.34 (d, 1H), 7.51 (dd, 1H); MS (APCI+)m/z 394 [M+H]⁺.

Step 4:6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 19 Step 3, 0.936 g, 2.38 mmol) was taken up in ammonia (7M inMeOH, 10 mL, 70.00 mmol) and the resulting mixture was bubbled withargon and then heated in the microwave reactor at 120° C. for 1 h. Thesolvent was evaporated. Ammonia (7M in MeOH, 6 mL, 42 mmol) was addedand the reaction was bubbled with argon and heated again using MW for 60min at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 10mL, 70 mmol) was added. The reaction was bubbled with argon and thenheated using MW for 2 h at 120° C. The solvent was evaporated andammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction washeated again for 2 h at 120° C. The solvent was evaporated and ammonia(7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heatedagain for 2 h at 120° C. The solvent was evaporated and ammonia (7M inMeOH, 20 mL, 140 mmol) was added. The reaction was heated again using MWfor 1 h at 120° C. The solvent was evaporated and the resulting residuewas taken up in DCM (60 mL) and brine (×2) and poured into a phaseseparator. The organic phase was dried with MgSO₄, filtered andevaporated to give the title compound (0.736 g, 82% yield) as a mixtureof isomers: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.09 (td, 1H), 1.27-1.49 (m,3H), 1.62-1.74 (m, 2H), 1.93-2.01 (m, 2H), 2.37 (s, 3H), 3.04-3.18 (m,3H), 3.34 (s, 3H), 6.90 (d, 1H), 7.20 (d, 1H), 7.38 (dd, 1H); MS(MM-ES+APCI)+ m/z 376 [M+H]⁺.

Separation of the isomers of6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Step 4, 80 mg, 0.21 mmol) was purified using preparativechromatography (Waters FractionLynx system equipped with a XBridge® PrepC8 10 μm OBD™ 19×250 mm column and a guard column; XTerra® Prep MS C810μm 19×10 mm Cartridge. A linear gradient of 35-70% MeOH in 0.2% NH₃ inMilliQ water was applied at flow rate of 20 mL/min) to give:

Isomeric mixture 1(1s,4s)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(the first to elute, minor isomer, 2.0 mg, 2.5% yield)

¹H NMR (500 MHz, CD₃CN) δ ppm 1.15-1.25 (m, 2H), 1.36 (td, 1H),1.45-1.59 (m, 2H), 1.63-1.74 (m, 3H), 2.19 (s, 3H), 2.98-3.06 (dd, 2H),3.20 (s, 3H), 3.32 (t, 1H), 5.19-5.39 (m, 2H), 6.75 (d, 1H), 7.20 (d,1H), 7.34 (dd, 1H); MS (ES+) m/z 378 [M+H]⁺.

and

Isomeric Mixture 2(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(the second to elute, major isomer, yield not determined)

¹H NMR (500 MHz, CDCl₃) δ ppm 1.09 (td, 3.47 Hz, 1H), 1.27-1.49 (m, 3H),1.62-1.74 (m, 2H), 1.93-2.01 (m, 2H), 2.37 (s, 3H), 3.04-3.18 (m, 3H),3.34 (s, 3H), 6.90 (d, 1H), 7.20 (d1H), 7.38 (dd, 1.73 Hz, 1H), MS(MM-ES+APCI)+ m/z 378 [M+H]⁺.

Separation of the isomers of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The isomers of Isomeric mixture 2 were separated using SFC BergerMultigram II, with a LuxC4; 4.6*250 mm; 5 μm column, and a mobile phaseconsisting of 15% McOH (containing 0.1% DEA) and 85% CO₂ at a flow rateof 50 mL/min to give:

Isomer 1:(1r,1′R,4R)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(9 mg, 11% yield) with retention time 6.1 min:

¹H NMR (500 MHz, CD₃CN) δ ppm 1.05 (dd, 1H), 1.23 (dt, 2H), 1.39 (d,1H), 1.49 (ddd, 2H), 1.81-1.89 (m, 2H), 2.17 (s, 3H), 2.94-3.10 (m, 3H),3.23 (s, 3H), 5.32 (br. s., 2H), 6.75 (d, 1H), 7.19 (d, 1H), 7.33 (dd,1H), MS (MM-ES+APCI)+ m/z 378 [M+H]⁺; and

Isomer 2:(1r,1′S,4S)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(15 mg, 19% yield) with retention time 9.5 min:

¹H NMR (500 MHz, CD₃CN) δ ppm 1.00-1.09 (m, 1H), 1.17-1.31 (m, 2H), 1.39(td, 1H), 1.50 (ddd, 2H), 1.86 (dt, 2H), 2.18 (s, 3H), 2.94-3.10 (m,3H), 3.24 (s, 3H), 5.32 (br. s., 2H), 6.76 (d, 1H), 7.20 (d, 1H), 7.34(dd, 1H), MS (MM-ES+APCI)+ m/z 378 [M+H]⁺.

Separation of the isomers of(1s,4s)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

1.7 g of a mixture containing(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(major) and(1s,4s)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(minor) was purified by preparative chromatography using the followingconditions: Column: XBridge C18; 50*300 mm; 10 μm, Mobile phase: 20-60%MeCN in 0.1% aq. NH₃ over 20 min, Flow rate: 120 mL/min. The obtainedminor isomer (equivalent to Isomeric mixture 1 above) with retentiontime 15 min, was then separated into its isomers by preparative SFCusing the following system: Berger Multigram II SFC system, Column:Chiralcel OD-H; 20*250 mm; 5 μm, Mobile phase: 10% MeOH (containing 0.1%DEA)/90% CO₂, Flow rate: 50 mL/min resulting in:

Isomer 3 with undetermined absolute configuration (77 mg, 5% yield) withretention time 6.5 min: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.17 (m,2H), 1.24 (td, 1H), 1.36-1.54 (m, 2H), 1.57-1.74 (m, 3H), 2.16 (s, 3H),2.85-3.07 (m, 2H), 3.12 (s, 3H), 3.29 (br. s., 1H), 6.58 (s, 2H), 6.63(d, 1H), 7.24 (d, 1H), 7.33 (dd, 1H); MS (APCI⁺) m/z 376 [M+H]⁺, and

Isomer 4 with undetermined absolute configuration (64 mg, 4% yield) withretention time 12 min: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05-1.17 (m,2H), 1.24 (td, 1H), 1.36-1.55 (m, 2H), 1.57-1.74 (m, 3H), 2.16 (s, 3H),2.85-3.06 (m, 2H), 3.12 (s, 3H), 3.29 (br. s., 1H), 6.58 (s, 2H), 6.63(d, 1H), 7.24 (d, 1H), 7.33 (dd, 1H); MS (APCI⁺) m/z 376 [M+H]⁺.

Method B Step 1:N-((1r,4r)-5′-Bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

(1r,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Method B Step 3, 31 g, 100 mmol),2-methylpropane-2-sulfinamide (15.8 g, 130 mmol),2-methyl-tetrahydrofuran (200 mL) and titanium ethoxide (41.3 mL, 200mmol) were heated to 100° C. to give an azeotrope at 74° C. Theazeotropic distillation was continued for 8 h and then the mixture wasreflux overnight. The azeotropic distillation was continued for anadditional 8 h and then the mixture was refluxed overnight. The mixturewas cooled to r.t. Additional 2-Me THF was added to give the originalconcentration of the mixture. A solution of sulfuric acid (11.14 mL,200.5 mmol) and Na₂SO₄ (35.6 g, 250 mmol) in water (150 mL) wasprepared. The reaction mixture was then added over 20 min to 4/5 of thevolume of the acidic solution. The phases were separated, and theorganic phase was washed with the remaining acidic solution, followed byammonium acetate (15.46 g, 200.5 mmol) in water (75 mL) and water (75mL). The organic phase was concentrated and dried in vacuo overnight togive the title compound (40.8 g, 99% yield): MS (ES+) m/z 412 [M+H]⁺.

Step 2:(1r,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-iminehydrochloride

HCl (2 M in Et₂O, 99 mL, 197 mmol) was added dropwise over 5 min toN-((1r,4r)-5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 19 Step 1, 40.8 g, 98.9 mmol) dissolved in Et₂O (30 mL) and DCM(30 mL). The mixture was stirred for 60 min before it was filtered. Thefilter cake was washed with Et₂O and dried in vacuo to give the titlecompound (31.3 g, 92% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.28 (m,2H) 1.70 (d, 2H) 2.04 (m, 4H) 3.17 (s, 2H) 3.23 (m, 1H) 3.28 (s, 3H)7.61 (d, 1H) 8.04 (dd, 1H) 8.81 (s, 1H); MS (EI) m/z 307 M⁺.

Step 3:(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-inden-1′,2′-imidazole]-4″(3″H)-thione

(1r,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-iminehydrochloride (Example 19 Step 2, 95 g, 200 mmol) (containing 30%(1s,4s)-6′-bromo-4-methoxyspiro-[cyclohexane-1,2′-inden]-1′(3′H)-iminehydrochloride) was portioned between DCM (600 mL) and 2 M aq. NaOH (400mL). The organic phase was concentrated and 2-propanol (200 mL) wasadded and the mixture was concentrated. The resulting(1r,4r)-6′-bromo-4-methoxyspiro-[cyclohexane-1,2′-inden]-1′(3′H)-imine,trimethyl orthoformate (66 mL, 602 mmol) and 2-propanol (300 mL) washeated to 80° C. 2-oxopropanethioamide (51.5 g, 500 mmol) in 2-propanol(250 mL) was added during 40 min while keeping the temperature above 65°C. The reaction was stirred at 75° C. for 2 h. The mixture wasconcentrated to ˜1/2 the volume and was left at 0° C. overnight. A solidwas formed that was filtered off, and dried in a vacuum cabinet at 40°C. for 3 h to give the title compound (61.24 g, 78% yield, containing14% of (1s,4s)-6′-bromo-4-m ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-inden-1′,2′-imidazole]-4″(3″H)-thione): MS (EI)m/z 392 M⁺.

Step 4:(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 19 Step 3, 22.7 g, 57.7 mmol) and ammonia (7 M in MeOH, 180 mL,1.26 mol) was put in a pressure reactor and heated to 74° C. overnight.The residue was allowed to reach r.t. and the mixture was concentrated.The residue was partitioned between 2 M citric acid (400 mL) and EtOAc(400 mL). Any insoluble material was filtered off and was determined tobe unreacted starting material. The organic phase (org 1) wasconcentrated in vacuo to give additional unreacted starting material. Tothe aqueous phase was EtOAc (300 mL) added and then 50% NaOH was addeduntil pH 12, and the mixture was stirred for 10 min. The resultingorganic phase (org 2) was saved. The residue from org 1, and the solidfiltered off were combined and suspended in ammonia (7 M in MeOH, 180mL, 1.26 mmol) and put in a pressure reactor and heated 100° C.overnight. The obtained solution was concentrated in vacuo. The residuewas partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL). Tothe aqueous phase was EtOAc (300 mL) added and then 50% NaOH was addeduntil pH 12, and the mixture was stirred for 10 min. The organic phasewas combined with org 2 from above. Activated charcoal was added to theorganic phase and the mixture was stirred for 30 min before it wasfiltered through diatomaceous earth. The organic phase was concentratedand dried in vacuo overnight to give a solid. To the solid wasdiisopropyl ether (125 mL) added and the mixture was refluxed overnight.The mixture was allowed to reach r.t. and the solid was filtered off togive the title compound (equivalent to Example 19 Isomeric Mixture 2above) (15 g, 69% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.93 (m, 1H)1.1-1.25 (m, 2H) 1.35-1.45 (m, 3H) 1.81 (br. d, 2H) 2.16 (s, 3H)2.87-3.03 (m, 3H) 3.18 (s, 3H) 6.59 (br. s., 2H), 6.64 (d, 1H), 7.25 (d,1H), 7.34 (dd, 1H); ES+) m/z 376 [M+H]⁺.

Step 5:(1r,1′R,4AR)-6′-Bromo-4-methoxy-5″methyl-3′H-dispiro[cyclohexane-1′,2″-indene-1′,2″imidazol]-4″-amine

To a 1 L round-bottomed flask was added(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 61 g, 162 mmol), EtOH (99.5%, 600 mL) andwater (60 mL) to give a homogeneous mixture which was heated to 70° C.The mixture was stirred for 30 min at the elevated temperature followedby addition of D(+)-10-camphorsulfonic acid (18.8 g, 81.0 mmol). Themixture was stirred at 70° C. for 3 h and then allowed to reach 20° C.over 2 h followed by stirring at 20° C. for 12 h. The mixture wasfiltered to give a solid that was dried in a vacuum oven at 50° C. for10 h to give the title compound as a D(+)-10-camphorsulfonic salt (37 g;37% yield). Enantiomeric ratio was determined by analysis on a SFCBerger Analytix system equipped with a Chiralpak AD-H column (4.6*250mm; 5 μm) and a mobile phase consisting of 10% MeOH (containing 0.1%DEA) and 90% CO₂ at a flow rate of 3 mL/min. The first peak withretention time 3.68 min (area 2.5%) corresponded to(1r,1′S,4S)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine,equivalent to Isomer 2. The second peak with retention time 4.58 min(area 97.5%) corresponded to the title compound(1r,1′R,4R)-6′-bromo-4-methoxy-5″methyl-3′H-dispiro[cyclohexane-1′,2″-indene-1′,2″imidazol]-4″-amine,equivalent to Isomer 1. The liberation of the title compound from thesalt was carried out by stirring the camphorsulfonic acid salt (0.32 g,0.53 mmol) suspended in dichloromethane (4 mL) with an aqueous solution(4 mL) of KOH (0.32 g, 5.7 mmol) at r.t. during 30 min. The organicphase was separated and concentrated in vacuo to give title compoundquantitatively with an enantiomeric excess of 95% (determined as above).

Method C(1r,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-iminehydrochloride

(1r,4r)-6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Step 3 Method C, 19.20 g at 91% NMR assay, 56.5 mmol) isreacted with 2-methylpropane-2-sulfinamide (8.90 g, 73.5 mmol) byheating with titanium (IV) ethoxide (24 mL, 115 mmol) and2-methyl-tetrahydrofuran (44 mL) at approximately 82° C. Three portionsof solvent (approximately 26 mL per portion) were distilled off after0.5 h, 7.5 h and 8 h periods of heating respectively, and more2-methyl-tetrahydrofuran (26 mL per portion, three portions) added aftercompleting each distillation. A further portion of solvent(approximately 26 mL) was distilled off after 17.5 h. The reactionmixture was cooled to r.t., diluted with DCM (52.5 mL) and then addedgradually to a solution (92 mL, 113 g) prepared from Na₂SO₄ (17.9% w/w),water (72.2% w/w) and sulfuric acid (9.9% w/w) over approximately 4 min.DCM (52.5 mL) was used to wash the reaction flask and addition funneland then added to the work-up flask. After separating the layers, theorganic phase was washed with a mixture of water (17.5 mL) and asolution (18.5 mL, 23 g) prepared from Na₂SO₄ (17.9% w/w), water (72.2%w/w) and sulfuric acid (9.9% w/w). The mixture was stirred with Na₂SO₄(8.75 g) for approximately 6 h. The slurry was filtered and the filtercake washed with DCM (17.5 mL). The combined filtrates were concentratedby distilling off the solvent (approximately 108 mL). Further DCM (52.5mL) was added and the same volume of solvent (52.5 mL) was distilledoff. The dry solution was cooled to approximately 20° C. and dilutedwith DCM (17.5 mL) and EtOH (8.7 mL). HCl (2 M in Et₂O) (34 mL, 68mmol), was then added gradually over approximately 20 min. The resultingslurry was held at approximately 20° C. for about 45 min beforefiltering. The filter cake was washed with a solution (17.5 mL perportion, three portions) prepared from equal volumes of DCM and Et₂O andthen dried in vacuo to give the title compound containing approximately4% of another isomer (17.41 g at 88% w/w NMR assay, 44.4 mmol, 79%yield) (residual DCM was detected at 6.8% w/w and ammonium chloride 2.9%w/w in the NMR assay): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.30 (m, 2H),1.70 (d, 2H), 1.98 (m, 2H), 2.10 (m, 2H), 3.17 (s, 2H), 3.23 (m, 1H),3.29 (s, 3H), 7.61 (d, 1H), 8.04 (dd, 1H), 8.75 (d, 1H), 12.90 (br s,2H).

Example 20a(1r,4r)-4-Methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

Method A

5-(Prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 0.044 g, 0.27mmol),(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method A Step 4, 0.085 g, 0.23 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) chloride (9.29 mg,0.01 mmol), K₂CO₃ (2M aq., 1.355 mL, 0.68 mmol) and2-methyl-tetrahydrofuran (0.5 mL) were mixed and heated to 100° C. usingMW for 2×30 min. 2-methyl-tetrahydrofuran (5 mL) and H₂O (5 mL) wereadded and the layers were separated. The organic layer was dried withMgSO₄ and then concentrated. The crude was dissolved in DCM and washedwith H₂O. The organic phase was separated through a phase separator anddried in vacuo. The crude product was purified with preparativechromatography. The solvent was evaporated and the H₂O-phase wasextracted with DCM. The organic phase was separated through a phaseseparator and dried to give the title compound (0.033 g, 36% yield), ¹HNMR (500 MHz, CD₃CN) δ ppm 1.04-1.13 (m, 1H), 1.23-1.35 (m, 2H), 1.44(td, 1H), 1.50-1.58 (m, 2H), 1.84-1.91 (m, 2H), 2.07 (s, 3H), 2.20 (s,3H), 3.00 (ddd, 1H), 3.08 (d, 1H), 3.16 (d, 1H), 3.25 (s, 3H), 5.25 (br.s., 2H), 6.88 (d, 1H), 7.39 (d, 1H), 7.49 (dd, 1H), 7.85 (t, 1H), 8.48(d, 1H), 8.64 (d, 1H), MS (MM-ES+APCI)+ m/z 413 [M+H]⁺.

Separation of the isomers of(1r,4r)-4-methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-4-Methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 20a, 0.144 g, 0.35 mmol) was purified using preparativechromatography (SFC Berger Multigram II, Column: Chiralcel OD-H; 20*250mm; 5 μm, mobile phase: 30% MeOH (containing 0.1% DEA); 70% CO₂, Flow:50 mL/min, total number of injections: 4). Fractions which contained theproduct were combined and the MeOH was evaporated to give:

Isomer 1:(1r,1′R,4R)-4-methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(49 mg, 34% yield) with retention time 2.5 min:

¹H NMR (500 MHz, CD₃CN) δ ppm 1.07-1.17 (m, 1H), 1.23-1.39 (m, 2H), 1.47(td, 1H), 1.57 (ddq, 2H), 1.86-1.94 (m, 2H), 2.09 (s, 3H), 2.23 (s, 3H),2.98-3.07 (m, 1H), 3.11 (d, 1H), 3.20 (d, 1H), 3.28 (s, 3H), 5.30 (hr.s., 2H), 6.91 (d, 1H), 7.42 (d, 1H), 7.52 (dd, 1H), 7.88 (t, 1H), 8.51(d, 1H), 8.67 (d, 1H), MS (MM-ES+APCI)+ m/z 413.2 [M+H]⁺; and

Isomer 2:(1r,1′S,4S)-4-methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(50 mg, 35% yield) with retention time 6.6 min:

¹H NMR (500 MHz, CD₃CN) δ ppm 1.02-1.13 (m, 1H), 1.20-1.35 (m, 2H), 1.44(d, 1H), 1.54 (ddd, 2H), 1.84-1.91 (m, 2H), 2.06 (s, 3H), 2.20 (s, 3H),3.00 (tt, 1H), 3.08 (d, 1H), 3.16 (d, 1H), 3.25 (s, 3H), 5.26 (br. s.,2H), 6.88 (d, 1H), 7.39 (d, 1H), 7.49 (dd, 1H), 7.84 (t, 1H), 8.48 (d,1H), 8.63 (d, 1H), MS (MM-ES+APCI)+ m/z 413.2 [M+H]⁺.

Method B

A vessel was charged with(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 7.5 g, 19.9 mmol),5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 3.37 g, 20.9mmol), 2.0 M aq. K₂CO₃ (29.9 mL, 59.8 mmol), and2-methyl-tetrahydrofuran (40 mL). The vessel was purged under vacuum andthe atmosphere was replaced with argon. Sodium tetrachloropalladate (II)(0.147 g, 0.50 mmol) and 3-(di-tert-butyl phosphonium) propane sulfonate(0.267 g, 1.00 mmol) were added and the contents were heated to refluxfor a period of 16 h. The contents were cooled to 30° C. and the phaseswere separated. The aqueous phase was extracted with2-methyl-tetrahydrofuran (2×10 mL), then the organics were combined,washed with brine and treated with activated charcoal (2.0 g). Themixture was filtered over diatomaceous earth, and then washed with2-methyl-tetrahydrofuran (20 mL). The filtrate was concentrated to avolume of approximately 50 mL, then water (300 μL) was added, and thecontents were stirred vigorously as seed material was added to promotecrystallization. The product began to crystallize and the mixture wasstirred for 2 h at r.t., then 30 min. at 0-5° C. in an ice bath beforebeing filtered. The filter cake was washed with 10 mL cold2-methyl-tetrahydrofuran and then dried in the vacuum oven at 45° C. togive the racemic title compound (5.2 g, 12.6 mmol, 63% yield): MS (ES+)m/z 413 [M+H]⁺.

(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(isomer 1)

Method C

A solution of(1r,4r)-4-methoxy-5″-methyl-6′-(5-prop-1-yn-1-ylpyridin-3-yl)-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 20a method B, 4.85 g, 11.76 mmol) and EtOH (75 mL) was stirredat 55° C. A solution of (+)-di-p-toluoyl-D-tartaric acid (2.271 g, 5.88mmol) in EtOH (20 mL) was added and stirring continued. After 2 min. aprecipitate began to form. The mixture was stirred for 2 h before beingslowly cooled to 30° C. and then stirred for a further 16 h. The heatwas removed and the mixture was stirred at r.t. for 30 min. The mixturewas filtered and the filter cake washed with chilled EtOH (45 mL). Thesolid was dried in the vacuum oven at 45° C. for 5 h, then the materialwas charged to a vessel and DCM (50 mL) and 2.0 M aq. NaOH solution (20mL) were added. The mixture was stirred at 25° C. for 15 min. The phaseswere separated and the aqueous layer was extracted with 10 mL DCM. Theorganic phase was concentrated in vacuo to a residue and 20 mL EtOH wasadded. The resulting solution was stirred at r.t. as water (15 mL) wasslowly added to the vessel. A precipitate slowly began to form, and theresulting mixture was stirred for 10 min. before additional water (20mL) was added. The mixture was stirred at r.t. for 1 h and thenfiltered. The filter cake was washed with water (15 mL) and dried in avacuum oven at 45° C. for a period of 16 h to give the title compound(1.78 g, 36% yield): MS (ES+) m/z 413 [M+H]⁺. This material isequivalent to Example 20a Isomer 1 above.

Method D

To a 500 mL round-bottomed flask was added(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-inden-1′,2′-imidazole]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Method B Step 5,25.4 g, 41.7 mmol), 2 M aq. KOH (100 mL) and 2-methyl-tetrahydrofuran(150 mL). The mixture was stirred for 30 min at r.t. after which themixture was transferred to a separatory funnel and allowed to settle.The phases were separated and the organic phase was washed with 2 M aq.K₂CO₃ (100 mL). The organic phase was transferred to a 500 mLround-bottomed flask followed by addition of5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 6.72 g, 41.74mmol), K₂CO₃ (2.0 M, 62.6 mL, 125.21 mmol). The mixture was degassed bymeans of bubbling Ar through the solution for 5 min. To the mixture wasthen added sodium tetrachloropalladate(II) (0.307 g, 1.04 mmol) and3-(di-tert-butylphosphonium)propane sulfonate (0.560 g, 2.09 mmol)followed by heating the mixture at reflux (80° C.) overnight. Thereaction mixture was allowed to cool down to r.t. and the phases wereseparated. The aqueous phase was extracted with 2-Me-THF (2×100 mL). Theorganics were combined, washed with brine and treated with activatedcharcoal. The mixture was filtered over diatomaceous earth and thefilter cake was washed with 2-Me-THF (2×20 mL), and the filtrate wasconcentrated to give 17.7 g that was combined with 2.8 g from otherruns. The material was dissolved in 2-Me-THF under warming and put onsilica (˜500 g). Elution with 2-Me-THF/Et₃N (100:0-97.5:2.5) gave theproduct. The solvent was evaporated, then co-evaporated with EtOH(absolute, 250 mL) to give (9.1 g, 53% yield). The HCl-salt was preparedto purify the product further: The product was dissolved in CH₂Cl₂ (125mL) under gentle warming, HCl in Et₂O (˜15 mL) in Et₂O (100 mL) wasadded, followed by addition of Et₂O (˜300 mL) to give a precipitate thatwas filtered off and washed with Et₂O to give the HCl-salt. CH₂Cl₂ and 2M aq. NaOH were added and the phases separated. The organic phase wasconcentrated and then co-evaporated with MeOH. The formed solid wasdried in a vacuum cabinet at 45° C. overnight to give the title compound(7.4 g, 43% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (d, 1H)1.12-1.30 (m, 2H) 1.37-1.51 (m, 3H) 1.83 (d, 2H) 2.09 (s, 3H) 2.17 (s,3H) 2.89-3.12 (m, 3H) 3.20 (s, 3H) 6.54 (s, 2H) 6.83 (s, 1H) 7.40 (d,1H) 7.54 (d, 1H) 7.90 (s, 1H) 8.51 (d, 1H) 8.67 (d, 1H); HRMS-TOF (ES+)m/z 413.2338 [M+H]⁺ (calculated 413.2341); enantiomeric purity >99.5%;NMR Strength 97.8±0.6% (not including water).

Example 20b(1r,4r)-4-Methoxy-5″-methyl-6′-[4-(prop-1-yn-1-yl)pyridin-2-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 50 mg, 0.13 mmol), potassium acetate (26.1mg, 0.27 mmol), bis(pinacolato)diboron (37.1 mg, 0.15 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (5.43 mg, 6.64 μmol) were taken up in dioxane(1 mL) in a microwave vial. The reaction vessel was sealed and heated at110° C. for 20 min in a Biotage Initiator. After cooling, K₂CO₃ (36.7mg, 0.27 mmol), Pd(Ph₃P)₄ (7.68 mg, 6.64 μmol), and water (0.300 mL)were added followed by 2-chloro-4-(prop-1-ynyl)pyridine (Intermediate32, 22.16 mg, 0.15 mmol) in dioxane (0.5 mL). The reaction vessel wassealed and heated at 110° C. for 30 min in a Biotage Initiator. Aftercooling, the mixture was filtered and concentrated in vacuo. The productwas purified by flash chromatography using a gradient of EtOAc inheptane (0-100%), then EtOAc:MeOH (9:1) to give the title compound (18mg, 32% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.95 (m, 1H), 1.12-1.31(m, 2H), 1.39-1.54 (m, 3H), 1.77-1.87 (m, 2H), 2.11 (s, 3H), 2.19 (s,3H), 2.90-3.12 (m, 3H), 3.20 (s, 3H), 6.56 (m, 2H), 7.25 (dd, 1H), 7.31(s, 1H), 7.38 (d, 1H), 7.78 (m, 1H), 7.88 (m, 1H), 8.55 (d, 1H); MS(MM-ES+APCI)+ m/z 413 [M+H]⁺.

Example 20c5-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]benzene-1,3-dicarbonitrile

The title compound (79 mg, 53% yield) was prepared as described forExample 20d starting from(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 133 mg, 0.35 mmol), and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isophthalonitrile (L.Echegoyen, F. Diederich et al. Eur. J. Org. Chem. 2007, 4659-4673) (135mg, 0.53 mmol): ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-1.04 (m, 1H),1.10-1.30 (m, 2H), 1.34-1.52 (m, 3H), 1.83 (d, 2H), 2.18 (s, 3H),2.86-3.13 (m, 3H), 3.19 (s, 3H), 6.54 (s, 2H), 6.96 (d, 1H), 7.43 (d,1H), 7.63 (dd, 1H), 8.34-8.42 (m, 3H); MS (APCI⁺) m/z 424 [M+H]⁺.

Example 20d3-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile

Method A

Sodium tetrachloropalladate(II) (3 mg, 10 μmol),3-(di-tert-butylphosphonium)propane sulfonate (5 mg, 0.02 mmol),(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 71 mg, 0.19 mmol),3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 35, 75 mg, 0.28 mmol), and 2 M aq. K₂CO₃ (0.29 mL, 0.57mmol) were mixed in dioxane (2 mL) and the mixture was degassed for acouple of min. by a stream of N₂ (g). The reaction mixture was heated atreflux for 2 h. Water and EtOAc were added and the phases wereseparated. The aqueous phase was extracted with EtOAc and the combinedorganic layers were dried over Na₂SO₄, filtered and evaporated. Thematerial was purified by flash chromatography (25 g silica, gradienteluent of EtOAc to a mixture of EtOAc/MeOH/conc. NH₃). The obtainedmaterial was purified by preparative chromatography. The pure fractionswere combined and the organic solvent was evaporated. The residue waspartitioned between 1 M aq. NaOH and EtOAc. The organic phase was dried(Na₂SO₄) and concentrated in vacuo to give the title compound (31 mg,38% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-1.03 (m, 1H), 1.10-1.31(m, 2H), 1.34-1.53 (m, 3H), 1.74-1.89 (m, 2H), 2.18 (s, 3H), 2.87-3.14(m, 3H), 3.19 (s, 3H), 6.55 (br. s., 2H), 6.89 (s, 1H), 7.41 (d, 1H),7.58 (dd, 1H), 7.95 (d, 2H), 8.01 (s, 1H); MS (APCI) m/z 433 [M+H]⁺.

3-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile(isomer 1)

Method B

The title compound was prepared as described for Example 20d abovestarting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Isomer 1) in two separate batches (143 mg, 0.38 mmol and 48mg, 0.13 mmol). After purification by flash chromatography andpreparative chromatography the product was freeze-dried fromacetonitrile and water. The obtained product was further dried in vacuoat 40° C. affording the title compound as a single enantiomer (127 mg,58% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (td, 1H), 1.10-1.30 (m,2H), 1.34-1.51 (m, 3H), 1.83 (d, 2H), 2.18 (s, 3H), 2.88-3.13 (m, 3H),3.19 (s, 3H), 6.55 (s, 2H), 6.89 (d, 1H), 7.41 (d, 1H), 7.58 (dd, 1H),7.95 (dt, 2H), 8.02 (t, 1H); MS (APCI) m/z 433 [M+H]⁺.

Method C

(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas a D(+)-10-camphorsulfonic acid salt (Example 19 Step 5, 36.6 g, 60.1mmol), 2-methyl-tetrahydrofuran (440 mL) and 2 M aq. KOH (330 mL) werestirred for 30 min. The organic phase was washed with 2 M aq. K₂CO₃ (148mL).3-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 35, 24.97 g, 62.5 mmol) and 2 M aqueous K₂CO₃ (90 mL,180.4 mmol) was added to the organic phase. The mixture was degassed.Sodium tetrachloropalladate(II) (0.456 g, 1.50 mmol) and3-(di-tert-butylphosphonium)propane sulfonate (0.832 g, 3.01 mmol) wasadded followed by heating to reflux under N₂(g). The mixture was stirredat reflux temperature for 220 min. To the mixture was added additional3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.600 g, 1.50 mmol) followed by reflux under N₂(g) for an additional140 min. The mixture was then allowed to attain 20° C. followed bystirring of the mixture for 30 min. at 20° C. To the mixture was addedwater (210 mL) and 2-Me-THF (211 mL) followed by stirring for 10 min.The organic phase was washed with brine (211 mL) and water (211 mL). Theorganic phase was distilled several times adding additional 2-Me-THF.The mixture was then concentrated to give a solid. The crude product waspurified by flash chromatography (SiO₂; 2% NH₃ in McOH, 2% McOH, 96%DCM; Rf=0.35) to give product as a solid. To the solid was added 99.5%EtOH (150 mL) followed by distillation of the mixture under reducedpressure to give a solid. The procedure was repeated 4 times. To thesolid was added 99.5% EtOH (270 mL). The mixture was heated to internalT=70° C. The mixture was cooled during 2 h to 45° C. during whichcrystallization took place followed by stirring at 45° C. for 6 h. Themixture was then allowed to reach 22° C. during 1 h and stirred at 22°C. for 2 h. The mixture was cooled to 5° C. and stirred for 3 h followedby filtration to give a solid which was washed with cold 99.5% EtOH (70mL) to give the product as a solid which was dried in a vacuum oven at50° C. for 20 h to give the title compound (15.66 g; 60% yield). Theenantiomeric excess was measured to 99.5% on a SFC Berger Analytixsystem equipped with a Chiralpak OD-H column (4.6*250 mm; 5 μm) and amobile phase consisting of 35% MeON (containing 0.1% DEA) and 65% CO₂.The first peak with retention time 1.87 min (area 99.75%) correspondedto the title compound3-[(1r,1′R,4R)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile.The second peak with retention time 4.08 min (area 0.25%) correspondedto3-[(1r,1′S,4S)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile:HRMS-TOF (ES+) m/z 433.1801 [M+H]+ (calculated: 433.1795); NMR strength90.0±0.2% (residual solvent ethanol was detected at 7.2±0.1%). Otheranalytical data (NMR, MS, HPLC) where in accordance to those previouslydescribed for the compound.

Example 20e(1r,4r)-6′-(5-Chloropyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

Method A

Sodium tetrachloropalladate(II) (3.13 mg, 10.63 μmol),3-(di-tert-butylphosphonium)propane sulfonate (5.71 mg, 0.02 mmol),(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19) (80 mg, 0.21 mmol) and 5-chloropyridin-3-ylboronic acid(35.2 mg, 0.21 mmol), was added to a vial. 2-Methyl-tetrahydrofuran (1mL) and K₂CO₃ (2M aq) (0.319 mL, 0.64 mmol) was added and the vial wasflushed with Ar (g) and capped. The mixture was heated in a microwavereactor at 90° C. for 30 min. Water was added and the residue wasextracted with EtOAc (×3). The organic phases were dried using a phaseseparator and concentrated. The crude product was purified withpreparative chromatography. The desired fractions were concentrated.Water and DCM were added and the phases were poured in to a phaseseparator. The organic phase was collected and concentrated in vacuo toyield the title compound (32 mg, 37% yield). ¹H NMR (500 MHz, DMSO-d₆) δppm 0.98 (td, 1H), 1.13-1.29 (m, 2H), 1.37-1.50 (m, 3H), 1.83 (d, 2H),2.17 (s, 3H), 2.91-2.98 (m, 1H), 3.00 (d, 1H), 3.09 (d, 1H), 3.20 (s,3H), 6.54 (br. s., 2H), 6.85-6.90 (m, 1H), 7.42 (d, 1H), 7.57 (dd, 1H),8.09 (t, 1H), 8.56 (d, 1H), 8.71 (d, 1H); MS (ES+) m/z 409 [M+H]⁺.

(1r,1′R,4R)-6′-(5-chloropyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(isomer 1)

Method B

Sodium tetrachloropalladate(II) (0.015 g, 0.05 mmol),3-(di-tert-butylphosphonium)propane sulfonate (0.014 g, 0.05 mmol),(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Isomer 1, 0.190 g, 0.50 mmol) and5-chloropyridin-3-ylboronic acid (0.100 g, 0.61 mmol) were added to avial. 2-Methyl-tetrahydrofuran (3 mL) and potassium carbonate (2M aq)(0.757 mL, 1.51 mmol) were added and the vial was flushed with Ar (g)and capped. The mixture was heated in a microwave reactor at 90° C. for30 min. Water was added and the residue was extracted with EtOAc (×3).The organic phases were combined and dried with MgSO₄ and concentrated.The crude product was purified using flash chromatography (25 g SiO₂, 5%isocratic 0.1 M NH₃ in MeOH in DCM). The fractions containing productwere combined and the solvent was evaporated to give the title compound(0.085 g, 41% yield). ¹H NMR (500 MHz, CD₃OD) δ ppm 1.06-1.21 (m, 1H),1.27-1.44 (m, 2H), 1.44-1.56 (m, 1H), 1.56-1.70 (m, 2H), 1.96 (d, 2H),2.33 (s, 3H), 3.09 (t, 1 H), 3.17 (d, 1H), 3.26 (d, 1H), 7.05 (s, 1H),7.50 (d, 1H), 7.59 (d, 1H), 8.03-8.09 (m, 1H), 8.49 (s, 1H), 8.65 (s,1H), MS (ES+) m/z 409 [M+H]⁺.

Example 20f(1r,4r)-6′-(5-Fluoropyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

5-Fluoropyridin-3-ylboronic acid (48 mg, 0.34 mmol) and precatalyst 13(see below) 8.36 mg, 10.63 μmol) was added to a microwave vial. The vialwas sealed and evacuated with argon (repeated 3 times).(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 80.0 mg, 0.21 mmol) dissolved in degassedTHF (0.5 mL) was added via a syringe. Degassed 0.5 M K₃PO₄ solution(1.276 mL, 0.64 mmol) was added via a syringe. The vial was heated in amicrowave reactor at 120° C. for 15 min. THF (1.5 mL) and precatalyst 13(FIG. 1) (8.36 mg, 10.63 μmol) was added. The reaction was evacuated andbackfilled with argon. The solution was stirred in r.t. for approx. 10min and then heated using MW for 15 min at 120° C. The solvent wasevaporated. The crude product was purified using preparativechromatography to give the title compound (34.5 mg, 41% yield), ¹H NMR(500 MHz, CD₃CN) δ ppm 1.05-1.14 (m, 1H), 1.23-1.35 (m, 2H), 1.44 (td,1H), 1.50-1.57 (m, 2H), 1.84-1.91 (m, 2H), 2.20 (s, 3H), 3.00 (tt, 1H),3.09 (d, 1H), 3.17 (d, 1H), 3.25 (s, 3H), 5.27 (br. s., 2H), 6.92 (d,1H), 7.41 (d, 1H), 7.51 (dd, 1H), 7.65-7.71 (m, 1H), 8.40 (d, 1H), 8.60(t, 1H), MS (MM-ES+APCI)+ m/z 393.2 [M+H]^(|).

For preparation of precatalyst 13 see: Kinzel, T.; Yong Zhang, Y.;Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073-14075.

Example 20g5-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-2-fluorobenzonitrile

Method A: The title compound (18 mg, 20% yield) was prepared asdescribed for Example 20e starting from(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 84 mg, 0.22 mmol) and3-cyano-4-fluorophenylboronic acid (40.5 mg, 0.25 mmol). ¹H NMR (500MHz, DMSO-d₆) δ ppm 0.97 (td, 1H), 1.13-1.28 (m, 2H), 1.37-1.50 (m, 3H),1.83 (d, 2H), 2.17 (s, 3H), 2.90-2.96 (m, 1H), 2.98 (d, 1H), 3.05-3.11(m, 1H), 3.20 (s, 3H), 6.53 (br s, 2H), 6.81-6.84 (m, 1H), 7.40 (d, 1H),7.49-7.57 (m, 2H), 7.89-7.95 (m, 1H), 8.10 (dd, 1H) MS (ES+) m/z 417[M+H]⁺.

5-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-2-fluorobenzonitrile(isomer 1)

Method B: The title compound (34 mg, 20% yield) was prepared using theprocedure in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 230 mg,0.38 mmol) and 3-cyano-4-fluorophenylboronic acid (74.8 mg, 0.45 mmol):¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (m, 1H), 1.21 (m, 2H), 1.46 (m,3H), 1.83 (d, 2H), 2.17 (s, 3H), 3.01 (m, 3H), 3.20 (s, 3H), 6.53 (br.s, 2H), 6.83 (d, 1H), 7.40 (d, 1H), 7.53 (m, 2H), 7.92 (m, 1H), 8.10(dd, 1H); MS (ES+) m/z 417 [M+H]⁺.

Example 20h(1r,4r)-6′-(3,3-Dimethylbut-1-yn-1-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

To a solution of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 0.157 g, 0.42 mmol) in DMF (8 mL) under anargon atmosphere was 3,3-dimethylbut-1-yne (0.045 g, 0.54 mmol),tetrakis(triphenylphosphine)palladium(0) (0.048 g, 0.04 mmol) andtriethylamine (1.75 mL, 12.5 mmol) added. The reaction mixture wasstirred at r.t. for 5 min. Cuprous iodide (0.012 g, 0.06 mmol) was addedand the reaction mixture was stirred overnight at 65° C. The reactionmixture to was allowed to reach r.t. and then partitioned between brineand EtOAc. The organic phase was dried over MgSO₄ and concentrated invacuo. The residue was purified by preparative chromatography to givethe title compound (0.047 g, 30% yield): ¹H NMR (500 MHz, DMSO-do) δ ppm0.82-0.97 (m, 1H), 1.24 (m, 11H), 1.34-1.48 (m, 3H), 1.81 (d, 2H), 2.15(s, 3H), 2.86-3.08 (m, 3H), 3.18 (s, 3H), 6.47 (s, 1H), 6.54 (s, 2H),7.14 (dd, 1H), 7.23 (d, 1H); MS (ES+) m/z 378 [M+H]⁺.

Separation of the isomers of(1r,4r)-6′-(3,3-dimethylbut-1-yn-1-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The isomers of(1r,4r)-6′-(3,3-dimethylbut-1-yn-1-yl)-4-methoxy-5″-methyl-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 20h, 0.047 g, 0.13 mmol) were separated using a SFC BergerMultigram 11 preparative HPLC, with a Chiralpak OD-H column (20*250 mm;5 μm), and a mobile phase consisting of 10% IPA (containing 0.1% DEA)and 90% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (16 mg, 33% yield)with retention time 4.9 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.84-0.98(m, 1H), 1.24 (m, 11H), 1.34-1.47 (m, 3H), 1.81 (d, 2H), 2.16 (s, 3H),2.88-3.06 (m, 3H), 3.18 (s, 3H), 6.47 (s, 1H), 6.54 (s, 2H), 7.14 (dd,1H), 7.23 (d, 1H); MS (ES+) m/z 378 [M+H]⁺; and

Isomer 2 with undetermined absolute configuration (16.0 mg, 34% yield)with retention time 6.7 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.81-0.99(m, 1H), 1.24 (m, 11H), 1.34-1.50 (m, 3H), 1.81 (d, 2H), 2.15 (s, 3H),2.87-3.07 (m, 3H), 3.18 (s, 3H), 6.47 (s, 1H), 6.54 (s, 2H), 7.09-7.18(m, 1H), 7.23 (d, 1H); MS (ES+) m/z 378 [M+H]⁺.

Example 20i(1r,4r)-6′-(cyclopropylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:(1r,4r)-6′-(Cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one

CuI (46.8 mg, 0.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (43.1 mg, 0.06 mmol) were weighed into a microwave vial. Thevial was capped and a solution of6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 5 Method A Step 3, 760 mg, 2.46 mmol) in THF (4 mL) wasadded, the vial was flushed with argon followed by sequential additionof ethynylcyclopropane (487 mg, 7.37 mmol) and triethylamine (1.028 mL,7.37 mmol). The reaction mixture was heated to 100° C. using MW for 1 h.CuI (56 mg), bis(triphenyl-phosphine)palladium(II) chloride (52 mg) andethynylcyclopropane (0.5 mL) were added and the mixture was heated to100° C. for 3 h. The reaction mixture was diluted with EtOAc and passedthrough a short plug of silica and further eluted with EtOAc. Theeluates were concentrated and the residue was dissolved in THF (15 mL)and added to a microwave vial containing CuI (62 mg),bis(triphenylphosphine)palladium(II) chloride (54 mg) and Cs₂CO₃ (1708mg, 5.24 mmol). The vial was flushed with argon and ethynylcyclopropane(0.5 mL) was added. The resulting mixture was heated to 100° C. using MWfor 90 min. CuI (60 mg), bis(triphenylphosphine)-palladium(II) chloride(57 mg) and ethynylcyclopropane (0.5 mL) were added and the mixture washeated to 100° C. for 1 h. The reaction mixture was diluted with EtOAc,passed through a short plug of silica and concentrated. The residue wascombined with a crude product from a previous batch of the same reaction(starting from 243 mg of6′-bromo-4-methoxyspiro-[cyclohexane-1,2′-inden]-1′(3′H)-one). Thecombined batches were purified by flash chromatography on silica using agradient elution with 0-30% EtOAc in heptane. The product was furtherpurified by preparative chromatography to afford 498 mg (52% yield) ofthe title compound: ¹H NMR (400 MHz, CDCl₃) δ ppm 0.78-0.84 (m, 2H),0.85-0.92 (m, 2H), 1.29-1.54 (m, 5H), 1.71-1.82 (m, 2H), 2.10-2.20 (m,2H), 3.01 (s, 2H), 3.21-3.32 (m, 1H), 3.40 (s, 3H), 7.36 (dd, 1H), 7.58(dd, 1H), 7.71-7.77 (m, 1H). MS (ES+) m/z 295 [M+H]⁺.

Step 2:N-((1r,4r)-5′-(Cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

(1r,4r)-6′-(Cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Example 20i Step 1, 494 mg, 1.68 mmol) and2-methylpropane-2-sulfinamide (366 mg, 3.02 mmol) were dissolved in 2-MeTHF (15 mL). Ti(OEt)₄ (0.704 mL, 3.36 mmol) was added and the resultingmixture heated to 80° C. for 70 h. The reaction mixture was cooled tor.t. and diluted with EtOAc (85 mL). Water (3 mL) was added undervigorous stirring and then the mixture was allowed to stand for 1 h. Themixture was filtered, the solvent was evaporated and the residuepurified by flash chromatography on silica using gradient elution 0-70%EtOAc/heptane to give 470 mg of the title compound (70% yield). ¹H NMR(500 MHz, CDCl₃) δ ppm 0.83 (m, 2H), 0.87 (m, 2H), 1.29-1.91 (m, 16H),2.12 (m, 2H), 3.00 (s, 2H), 3.20-3.33 (m, 1H), 3.40 (s, 3H), 7.27 and7.29 (m overlapping with solvent, 2H), 7.49 (dd, 1H). MS (ES+) m/z 398[M+H]⁺.

Step 3:6′-(Cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

4 M HCl in dioxane (1.5 mL, 6.00 mmol) was added to a solution ofN-(5′-(cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 20i Step 2, 470 mg, 1.18 mmol) in dry dioxane (5 mL) at 5° C.The reaction mixture was allowed to come to r.t. and stirred for 1 h,then it was stored at 0° C. overnight and then concentrated. The product(as the hydrochloride salt) was dissolved in DCM and washed with aq.sat. NaHCO₃, dried over Na₂SO₄ and concentrated to give 363 mg of thetitle compound (quantitative yield). ¹H NMR (500 MHz, CDCl₃) δ ppm0.78-0.85 (m, 2H), 0.85-0.91 (m, 2H), 1.34-1.49 (m, 3H), 1.54-1.63 (m,2H), 1.68-1.84 (m, 2H), 2.08-2.19 (m, 2H), 2.98 (s, 2H), 3.23-3.33 (m,1H), 3.38-3.43 (m, 3H), 7.27 (m, 2H), 7.46 (dd, 1H), 7.69 (br. s., 1H).MS (ES+) m/z 294 [M+H]⁺.

Step 4:(1r,4r)-6′-(cyclopropylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

A mixture of6′-(cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 20i Step 3, 360 mg, 1.23 mmol) and 2-oxopropanethioamide(Intermediate 2, 380 mg, 3.68 mmol) in anhydrous MeOH (10 mL) was heatedto 60° C. under an argon atmosphere for 18 h. The mixture wasconcentrated and 7 M solution of ammonia in MeOH (20 mL, 140 mmol) wasadded. The resulting mixture was heated to 120° C. using MW for 45 min.The reaction mixture was concentrated, another portion of 7 M ammonia inMcOH (20 mL, 140 mmol) was added to the residue and the mixture washeated using MW to 120° C. for 45 min. This cycle of concentration,ammonia addition and heating was repeated twice more. The reactionmixture was concentrated, the residue was dissolved in DCM and passedthrough a plug of silica which was further eluted with DCM/EtOAc(50:50). The fractions containing the desired product were concentratedand the residue was further purified by HPLC to give 85 mg (19% yield)of the title compound: ¹H NMR (500 MHz, CDCl₃) δ ppm 0.71-0.76 (m, 2H),0.79-0.85 (m, 2H), 1.09 (td, 1H), 1.26-1.42 (m, 3H), 1.42-1.50 (m, 1H),1.60-1.71 (m, 2H), 1.87-2.00 (m, 2H), 2.27 (s, 3H), 3.02-3.10 (m, 1H),3.10-3.19 (m, 2H), 3.33 (s, 3H), 6.76 (s, 1H), 7.20 (d, 1H), 7.24 (dd,1H); MS (ES+) m/z 362 [M+H]⁺, (ES−) m/z 360 [M−H]⁻.

Separation of the isomers of(1r,4r)-6′-(cyclopropylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The isomers of(1r,4r)-6′-(cyclopropylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 20i Step 4, 65 mg, 0.18 mmol) were separated using a SFC BergerMultigram II preparative HPLC, with a Chiralpak OD-H; 20*250 mm; 5 μmcolumn, and a mobile phase consisting of 20% MeOH (containing 0.1% DEA)and 80% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (22 mg, 35% yield)with retention time 2.9 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.67 (m,2H), 0.83 (m, 2H), 0.93 (br. s., 1H), 1.18 (m, 2H), 1.43 (m, 4H), 1.80(m, 2H), 2.15 (s, 3H), 2.96 (m, 3H), 3.18 (s, 3H), 6.48 (s, 1H), 6.53(s, 2H), 7.15 (dd, 1H), 7.23 (d, 1H); MS (APCI+) m/z 362 [M+H]⁺. and

Isomer 2 with undetermined absolute configuration (22 mg, 35% yield)with retention time 4.0 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.67 (m,2H), 0.83 (m, 2H), 0.93 (m, 1H), 1.18 (m, 2H), 1.42 (m, 4H), 1.80 (m,2H), 2.15 (s, 3H), 2.97 (m, 3H), 3.18 (s, 3H), 6.48 (s, 1H), 6.53 (s,2H), 7.15 (dd, 1H), 7.23 (d, 1H); MS (APCI+) m/z 362 [M+H]⁺.

Example 20jN-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-bromopyrimidine-2-carboxamideStep 1:(1r,4r)-4-Methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 156 mg, 0.41 mmol),trans-4-hydroxypyrrolidine-2-carboxylic acid (54.4 mg, 0.41 mmol),copper(I) iodide (39.5 mg, 0.21 mmol) and K₂CO₃ (172 mg, 1.24 mmol) weremixed in dry dimethylsulfoxide (3 mL) in a microwave vial. The mixturewas stirred under argon at r.t. for 30 min. Ammonia, 30-33% in H₂O(0.389 mL, 6.22 mmol) was added, the vial was sealed and heated at 110°C. for 3 h in a microwave synthesizer. The reaction was diluted withEtOAc (25 mL) and washed with brine (25 mL). The aqueous layer wasextracted with EtOAc (2×25 mL). The organics were combined, dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography on silica gel using a gradient of0%-100% (10% MeOH in DCM containing 0.1 N NH₃) in DCM to give the titlecompound (99 mg, 76% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.86 (td,1H), 1.07-1.25 (m, 2H), 1.33-1.50 (m, 2H), 1.79 (m, 2H), 2.12 (s, 3H),2.80 (m, 2H), 2.91 (m, 1H), 3.18 (s, 3H), 4.71 (s, 2H), 5.82 (d, 1H),6.35 (dd, 1H), 6.41 (s, 2H), 6.89 (d, 1H); MS (ES+) m/z 313 [M+H]⁺.

Step 2:N-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-bromopyrimidine-2-carboxamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (45.5 mg,0.24 mmol) was added to a suspension of 5-bromopyrimidine-2-carboxylicacid (44.4 mg, 0.22 mmol) in DCM m (0.5 mL). The obtained solution wasstirred for 5 min and added dropwise over 2 min to an ice-cooledsolution of(1r,4r)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine(Example 20j Step 1, 57 mg, 0.18 mmol) and 2M HCl (0.091 mL, 0.18 mmol)in DMF (0.500 mL). The mixture was stirred at 0° C. for 10 min and thenallowed to reach r.t. overnight. The solvent was evaporated. The crudewas purified using preparative chromatography to give the title compound(10 mg, 11% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.85-1.00 (m, 1H),1.08-1.31 (m, 2H), 1.38-1.52 (m, 3H), 1.77-1.87 (m, 2H), 2.16 (s, 3H),2.87-3.06 (m, 3H), 3.19 (s, 3H), 6.50-6.60 (m, 2H), 7.15-7.20 (m, 1H),7.22-7.29 (m, 1H), 7.50-7.63 (m, 1H), 9.18 (s, 2H), 10.53-10.64 (m, 1H).MS (ES+) m/z 497.1 [M+H]⁺.

Example 20kN-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-(trifluoromethyl)pyridine-2-carboxamide

Xantphos (20.76 mg, 0.04 mmol), cesium carbonate (156 mg, 0.48 mmol),palladium(II) acetate (8.05 mg, 0.04 mmol) and5-(trifluoromethyl)picolinamide (79 mg, 0.42 mmol) were added to amicrowave vial. The vial was flushed with argon. A solution of6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method A Step 4, 90 mg, 0.24 mmol) in dry THF (1.4 mL) wasadded. The reaction was heated using MW at 150° C. for 1 h. Xantphos(20.76 mg, 0.04 mmol) and palladium(II) acetate (8.05 mg, 0.04 mmol)were added and the reaction was heated again for 1 h at 150° C. The sameprocedure with addition of Xantphos and Pd(OAc)₂ and heating wasrepeated once more. The solvent was evaporated and the crude product wasdissolved in DCM. The mixture was extracted with brine and filteredthrough a phase separator. The solvent was evaporated. The crude productwas purified using flash chromatography (12 g SiO₂, 0-10% 0.1 M NH₃ inMeOH in DCM). The fractions containing product were combined and thesolvent was evaporated. The product was further purified usingpreparative chromatography to give the title compound (10 mg, 9% yield).¹H NMR (500 MHz, CDCl₃) δ ppm 1.09 (td, 1H), 1.30-1.42 (m, 2H),1.52-1.62 (m, 1H), 1.63-1.78 (m, 2H), 1.91-2.01 (m, 2H), 2.34 (s, 3H),3.03-3.13 (m, 1H), 3.13-3.24 (m, 2H), 3.34 (s, 3H), 7.35 (d, 1H), 7.54(dd, 1H), 8.15 (dd, 1H), 8.37 (d, 1H), 8.85 (s, 1H), 9.87 (s, 1H); MS(ES+) m/z 486 [M+H]⁺.

Example 20n

N-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-6-chloro-3-methyl-1-benzofuran-2-carboxamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (45.5 mg,0.24 mmol) was added to a suspension of5-chloro-3-methylbenzofuran-2-carboxylic acid (46.1 mg, 0.22 mmol) inDCM (0.5 mL). The obtained solution was stirred for 5 min and then addeddropwise over 2 min to an ice-cooled solution of(1r,4r)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine(Example 20j Step 1, 57 mg, 0.18 mmol) and 2M HCl (0.091 mL, 0.18 mmol)in DMF (0.500 mL). The mixture was stirred at 0° C. for 10 min and wasthen allowed to reach r.t. overnight. The solvent was evaporated. Thecrude product was purified using preparative chromatography to give thetitle compound (7 mg, 8% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.86-0.97 (m, 1H), 1.08-1.32 (m, 2H), 1.41-1.51 (m, 3H), 1.79-1.87 (m,2H), 2.18 (s, 3H), 2.54 (s, 3H), 2.89-3.08 (m, 3H), 3.21 (s, 3H), 6.57(br. s, 2H), 7.15 (s, 1H), 7.23-7.29 (m, 1H), 7.51-7.55 (m, 1H),7.56-7.60 (m, 1H), 7.66 (s, 1H), 7.91 (d, 1H), 10.28 (s, 1H). MS (ES+)m/z 505.2 [M+H]⁺.

Example 20oN-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-3,5-dichloropyridine-2-carboxamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (55.8 mg,0.29 mmol) was added to a suspension of 3,5-dichloropicolinic acid (43.0mg, 0.22 mmol) in DCM (0.5 mL). The obtained solution was stirred for 5min and added dropwise over 2 min to an ice-cooled solution of4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine(Example 20j Step 1, 70 mg, 0.22 mmol) and 2M HCl (0.112 mL, 0.22 mmol)in DMF (0.5 mL). The mixture was stirred at 0° C. for 60 min. Themixture was stirred at r.t. for 2 days before the mixture wasconcentrated and diluted with DMSO and purified by preparativechromatography. The fractions were pooled and extracted with DCM (×3),and the organic phase was passed through a phase separator. Removal ofthe solvent provided the title compound (19.5 mg, 18% yield): ¹H NMR(500 MHz, CDCl₃) δ ppm 1.06 (td, J=13.56, 3.78 Hz, 1H), 1.26-1.43 (m,2H), 1.56 (td, J=13.56, 3.15 Hz, 1H), 1.61-1.73 (m, 2H), 1.89-1.99 (m,2H), 2.31 (s, 3H), 3.03-3.10 (m, 1H), 3.10-3.20 (m, 2H), 3.33 (s, 3H),7.25 (d, J=1.89 Hz, 1H), 7.31 (d, J=8.20 Hz, 1H), 7.41 (d, J=8.20 Hz,1H), 7.87 (d, J=1.89 Hz, 1H), 8.44 (d, J=2.21 Hz, 1H), 9.66 (s, 1H); MS(ES+) m/z 486 [M+H]⁺.

Example 20qN-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chloropyridine-2-carboxamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (37.5 mg,0.20 mmol) was added to a suspension of 5-chloropicolinic acid (28.4 mg,0.18 mmol) in DCM (0.5 mL). The solution was stirred for 5 min at r.t.and then dropwise added over 2 min to an ice-cooled solution of4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine (Example 20j, step 1, 47 mg, 0.15 mmol) and 2M HCl(0.075 mL, 0.15 mmol) in DMF (0.500 mL). The mixture was stirred at 0°C. for 2 min. The solvent was evaporated. The crude product was purifiedusing preparative chromatography. The fractions containing the pureproduct were collected and extracted with DCM, dried through a phaseseparator and evaporated to give the title compound (31.5 mg, 46%yield). ¹H NMR (500 MHz, CD₃CN) δ ppm 1.04 (td, 1H), 1.17-1.28 (m, 2H),1.45 (td, 1H), 1.53 (d, 2H), 1.83-1.89 (m, 2H), 2.19 (s, 3H), 2.93-3.06(m, 2H), 3.06-3.18 (m, 1H), 3.24 (s, 3H), 5.27 (br. s., 2H), 7.14 (d,1H), 7.27 (d, 1H), 7.48 (dd, 1H), 7.99 (dd, 1H), 8.15 (d, 1H), 8.63 (d,1H), 9.80 (br. s., 1H), MS (ES+) m/z 452 [M+H]⁺.

Example 20t(1r,4r)-4-Methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-((1r,4r)-5′-Isobutoxy-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

(1r,4r)-6′-Isobutoxy-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 69, 1.24 g, 4.10 mmol) and 2-methylpropane-2-sulfinamide(0.895 g, 7.38 mmol) were dissolved in 2-methyl-tetrahydrofuran (15 mL)and titanium(IV) ethoxide (1.72 mL, 8.20 mmol) was added. The resultingmixture was heated to reflux overnight. More2-methylpropane-2-sulfinamide (0.45 g, 3.7 mmol) was added and thereaction was continued. After another day, the mixture was allowed tocool to r.t. EtOAc (35 mL) was added followed by dropwise addition ofwater (15 mL) under vigorous stirring. After 10 min of stirring themixture was allowed to stand still for 1 h before the formed solids werefiltered off. The organic layer was dried over Na₂SO₄ and concentratedin vacuo. Purification by flash chromatography using a gradient of 0-20%EtOAc in heptane as eluent afforded 1.036 g (62% yield) of the titlecompound: ¹H NMR (500 MHz, CDCl₃) δ 1.01-1.07 (m, 6H), 1.31-1.36 (s,9H), 1.36-1.46 (m, 2H), 1.52-1.67 (m, 4H), 2.07-2.14 (m, 3H), 2.96 (s,2H), 3.22-3.33 (m, 1H), 3.38-3.42 (m, 3H), 3.73-3.84 (m, 2H), 7.10 (dd,1H), 7.25 (s, 1H), 7.75-8.03 (m, 1H); MS (ES+) m/z 406 [M+H]⁺.

Step 2:(1r,4r)-6′-Isobutoxy-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4 M in 1,4-dioxane, 6.4 mL, 25.5 mmol) was added to a solution ofN-((1r,4r)-5′-isobutoxy-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 20t, Step 1, 1.036 g, 2.55 mmol) in anhydrous 1,4-dioxane (3mL). The resulting mixture was stirred under N₂ at r.t. for 1 h. Themixture was concentrated to one third of the volume and Et₂O (40 mL) wasadded. The formed solid was filtered off and washed with Et₂O. The solidwas partitioned between DCM and sat. aq. NaHCO₃. The phases wereseparated and the organic layer dried over Na₂SO₄ and concentrated invacuo. The product (635 mg, 82% yield) was used immediately as such inthe next step: MS (EI) m/z 301 M⁺.

Step 3:(1r,41)-4-Methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

2-Oxopropanethioamide (Intermediate 2, 652 mg, 6.32 mmol) and(1r,4r)-6′-isobutoxy-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 20t, Step 2, 635 mg, 2.11 mmol) were dissolved in dry MeOH (10mL) and the resulting solution was heated at 60° C. under a nitrogenatmosphere overnight. The mixture was allowed to cool to r.t. and thesolvent was evaporated in vacuo. Purification by flash chromatographyusing a gradient of 0-40% EtOAc in heptane as eluent afforded 678 mg(83% yield) of the title compound: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.00(d, 6H), 1.12-1.48 (m, 5H), 1.56-1.80 (m, 3H), 2.01-2.09 (m, 1H), 2.40(s, 3H), 3.06 (s, 2H), 3.03-3.14 (m, 1H), 3.35 (s, 3H), 3.63 (d, 2H),6.43 (d, 1H), 6.86 (dd, 1H), 7.21 (d, 1H), 8.69 (s, 1H); MS (ES+) m/z387 [M+H]⁺.

Step 4:(1r,4r)-4-Methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-4-Methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 20t Step 3, 678 mg, 1.75 mmol) and ammonia (7 M in MeOH, 15 mL,105 mmol) were mixed in a microwave vial. The vial was sealed and thereaction was heated at 100° C. for 30 min in a microwave reactor (fixedhold time). The mixture was concentrated in vacuo and the residue wasdissolved in ammonia (7 M in MeOH, 15 mL, 105 mmol) and heated at 100°C. for 30 min in a microwave reactor. This (concentration, addition ofammonia and heating) was repeated twice (4 runs in total). Afterevaporation of the solvent, the residue was partitioned between EtOAcand 2 M citric acid. The phases were separated and the organic layer wasextracted with 2 M citric acid. The organic layer was discarded whilethe combined aqueous phases were basified to pH 12 by addition of 50%NaOH (aq). The product was extracted with EtOAc (×2). The combinedorganic layers were treated with charcoal and filtered throughdiatomaceous earth. The filter pad was rinsed with EtOAc and thefiltrate was concentrated in vacuo to give 432 mg (67% yield) of thetitle compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.89 (d, 1H), 0.93 (d,6H), 1.08-1.26 (m, 2H), 1.35-1.49 (m, 3H), 1.80 (d, 2H), 1.86-1.97 (m,1H), 2.15 (s, 3H), 2.81-2.98 (m, 3H), 3.18 (s, 3H), 3.58 (dd, 2H), 6.05(d, 1H), 6.50 (br. s., 2H), 6.70 (dd, 1H), 7.15 (d, 1H); MS (ES+) m/z370 [M+H]⁺.

Separation of the isomers of(1r,4r)-4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The isomers of(1r,4r)-4-methoxy-5″-methyl-6′-(2-methylpropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 20t Step 4, 376 mg, 1.02 mmol) were separated using a SFCBerger Multigram II preparative HPLC equipped with a LuxC4 (20*250 mm; 5μm) column, and a mobile phase consisting of 30% MeOH (containing 0.1%DEA) and 70% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (128 mg, 34% yield)with retention time 2.6 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.89 (d,1H), 0.93 (d, 6H), 1.08-1.27 (m, 2H), 1.35-1.47 (m, 3H), 1.80 (d, 2H),1.86-1.98 (m, 1H), 2.14 (s, 3H), 2.82-2.99 (m, 3H), 3.18 (s, 3H), 3.58(dd, 2H), 6.05 (d, 1H), 6.50 (s, 2H), 6.70 (dd, 1H), 7.14 (d, 1H); MS(ES+) m/z 370 [M+H]⁺; andIsomer 2 with undetermined absolute configuration (146 mg, 39% yield)with retention time 3.5 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.89 (d,1H), 0.93 (d, 6H), 1.08-1.26 (m, 2H), 1.35-1.47 (m, 3H), 1.80 (d, 2H),1.87-1.98 (m, 1H), 2.15 (s, 3H), 2.81-2.98 (m, 3H), 3.18 (s, 3H), 3.58(dd, 2H), 6.05 (d, 1H), 6.50 (s, 2H), 6.70 (dd, 1H), 7.14 (d, 1H). MS(ES+) m/z 370 [M+H]⁺.

Example 20u(1r,4r)-4-methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-[(1r,1′E,4r)-4-Methoxy-6′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-ylidene]-2-methylpropane-2-sulfinamide

(1r,4r)-4-Methoxy-6′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 83, 320 mg, 0.93 mmol) and 2-methylpropane-2-sulfinamide(204 mg, 1.68 mmol) were dissolved in 2-methyl-tetrahydrofuran (4 mL).Titanium(IV) ethoxide (0.391 mL, 1.87 mmol) was added. The resultingmixture was heated at reflux over the weekend. The mixture was allowedto cool to r.t. and EtOAc (10 mL) was added followed by dropwiseaddition of water (5 mL) under vigorous stirring. After 10 min ofstirring the mixture was allowed to stand still for 1 h before theformed solids were filtered off. The organic layer was dried over Na₂SO₄and concentrated. Purification of the crude product by flashchromatography using 0-20% EtOAc in heptane as eluent afforded 270 mg(65% yield) of the title compound (containing 5% of another isomer): ¹HNMR (500 MHz, CDCl₃) δ 1.32-1.35 (m, 9H), 1.36-1.45 (m, 2H), 1.52-1.57(m, 1H), 1.60-1.68 (m, 1H), 1.72-2.07 (m, 2H), 2.13 (d, 2H), 2.63 (dt,2H), 2.97 (s, 2H), 3.21-3.32 (m, 1H), 3.40 (s, 3H), 4.26 (td, 2H), 7.11(dd, 1H), 7.29 (d, 1H), 7.87-8.13 (m, 1H); MS (ES+) m/z 446 [M+H]⁺.

Step 2:(1r,4r)-4-Methoxy-6′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4 Min 1,4-dioxane) (1.52 mL, 6.06 mmol) was added to a solution ofN-((1r,4r)-4-methoxy-5′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 20u Step 1, 270 mg, 0.61 mmol) in anhydrous 1,4-dioxane (1 mL).The resulting mixture was stirred under N₂ at r.t. for 2 h. The mixturewas concentrated to 1/3 of the volume and Et₂O (40 mL) was added. Asolid was formed which was filtered off and washed with Et₂O. The solidwas partitioned between DCM and sat. aq. NaHCO₃. The phases wereseparated and the organic layer dried over Na₂SO₄ and concentrated invacuo. The product (174 mg, 84% yield) containing 9% of another isomerwas used immediately as such in the next step: MS (ES+) m/z 342 [M+H]⁺.

Step 3:(1r,4r)-4-Methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

2-Oxopropanethioamide (Intermediate 2, 158 mg, 1.53 mmol) and4-methoxy-6′-(3,3,3-trifluoropropoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 20u, Step 2, 174 mg, 0.51 mmol) were dissolved in dry MeOH (3mL) and the resulting orange solution was heated at 60° C. under anitrogen atmosphere overnight. The mixture was allowed to cool to r.t.and the solvent was evaporated in vacuo. Purification by flashchromatography using a gradient of 0-30% EtOAc in heptane as eluentafforded 175 mg (81% yield) of the title compound containing 5% ofanother isomer: ¹H NMR (500 MHz, CDCl₃) 1.15-1.24 (m, 1H), 1.34-1.53 (m,2H), 1.56-1.69 (m, 2H), 1.75 (dd, 1H), 2.02 (dt, 2H), 2.40 (s, 3H),2.53-2.64 (m, 2H), 3.08 (s, 2H), 3.09-3.13 (m, 1H), 3.35 (s, 3H), 4.12(t, 2H), 6.44 (s, 1H), 6.87 (d, 1H), 7.24 (d, 1H), 8.84 (br. s., 1H); MS(ES+) m/z 387 [M+H]⁺.

Step 4:(1r,4r)-4-methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-4-Methoxy-5″-methyl-6′-(3,3,3-trifluoropropoxy)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 20u Step 3, 175 mg, 0.41 mmol) and ammonia (7 M in McOH, 3 mL,21 mmol) were mixed in a microwave vial. The vial was scaled and thereaction was heated at 110° C. for 30 min in a microwave reactor. Themixture was concentrated in vacuo and the residue was dissolved inammonia (7 M in MeOH, 3 mL, 21 mmol) and heated at 110° C. for 30 min ina microwave reactor. This procedure (concentration, addition of ammoniaand heating) was repeated twice (4 runs in total). After evaporation ofthe solvent, the residue was partitioned between EtOAc and 2 M aq.citric acid. The phases were separated and the organic layer wasextracted with 2 M citric acid. The organic layer was discarded whilethe combined aqueous phases were basified to pH 12 by addition of 50%aq. NaOH. The product was extracted with EtOAc (twice). The combinedorganic layers were treated with charcoal and filtered throughdiatomaceous earth. The filter pad was rinsed with EtOAc and thefiltrate was concentrated in vacuo. Purification by preparativechromatography afforded 64 mg (38% yield) of the title compound: ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.90 (td, 1H), 1.08-1.27 (m, 2H), 1.34-1.49 (m,3H), 1.80 (d, 2H), 2.15 (s, 3H), 2.69 (tt, 2H), 2.82-2.99 (m, 3H),3.15-3.22 (m, 3H), 4.00-4.10 (m, 2H), 6.08 (d, 1H), 6.51 (br. s., 2H),6.75 (dd, 1H), 7.18 (d, 1H); MS (APCI+) m/z 410 [M+H]⁺.

Example 20v(1r,4r)-6′-(3-Fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-(5′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

6′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 65, 611 mg, 1.99 mmol) and 2-methylpropane-2-sulfinamide(435 mg, 3.59 mmol) were dissolved in 2-methyl-tetrahydrofuran (40 mL).Titanium(IV) ethoxide (0.84 mL, 3.99 mmol) was added and the resultingmixture was heated to 80° C. over a weekend. The reaction mixture wascooled to r.t. and diluted with EtOAc (85 mL). Water (3 mL) was addedunder vigorous stirring and then the mixture was allowed to stand for 1h. The mixture was filtered, the solvent was evaporated, and the residuewas purified by flash chromatography using a gradient of EtOAc (0-70%)in heptane to give 244 mg (30% yield) of the title compound: MS (ES+)m/z 410 [M+H]⁺.

Step 2:6′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4 M in 1,4-dioxane, 1.489 mL, 5.96 mmol) was added to a solution ofN-(5′-(3-fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 20v, Step 1, 244 mg, 0.60 mmol) in anhydrous 1,4-dioxane (25mL). A white precipitate was formed immediately and the resulting cloudymixture was stirred under a nitrogen atmosphere overnight. The mixturewas diluted with NaHCO₃ (aq) and extracted with DCM, dried over MgSO₄and concentrated in vacuo to give 204 mg (quantitative yield) of thetitle compound that was used without any purification in the next step:MS (ES+) m/z 306 [M+H]⁺.

Step 3:6′-(3-Fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

6′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 20v, Step 2, 204 mg, 0.67 mmol), trimethyl orthoformate (0.193mL, 1.76 mmol) and 2-propanol (5 mL) was added to a MW vial. The vialwas sealed and the mixture was heated at 60° C. (oil bath).2-Oxopropanethioamide (Intermediate 2, 138 mg, 1.34 mmol) in MeOH (15mL) was added and the resulting mixture was stirred overnight at 60° C.and was then concentrated in vacuo. The product was isolated using flashchromatography (0-50% EtOAc in heptane) to give the title compound (167mg, 64% yield): MS (ES+) m/z 391 [M+H]⁺. Step 4:(1r,4r)-6′-(3-Fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

6′-(3-Fluoropropoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 20v, Step 3, 167 mg, 0.43 mmol) was placed into a microwavevial. Ammonia (7M in MeOH, 2 mL, 14 mmol) was added. The mixture washeated for 30 min at 90° C. in a microwave reactor. The mixture wasconcentrated and ammonia (7M in MeOH, 2 mL, 14 mmol) was added. Themixture was heated at 120° C. for 30 min in a microwave reactor. Thecycle of concentration, addition of ammonia and heating at 120° C. withMW was repeated 5 times. The mixture was concentrated in vacuo. Theproduct was isolated using preparative chromatography to give 40 mg (25%yield) of the title compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.93 (td,J=13.40, 2.84 Hz, 1H) 1.07-1.27 (m, 2H) 1.31-1.48 (m, 3H) 1.81 (d,J=9.46 Hz, 2H) 1.95-2.10 (m, 2H) 2.17 (s, 3H) 2.83-2.99 (m, 3H) 3.18 (s,3H) 3.88-3.95 (m, 2H) 4.51 (t, J=5.99 Hz, 1H) 4.61 (t, J=5.99 Hz, 1H)6.14 (d, J=2.21 Hz, 1H) 6.75 (dd, J=8.20, 2.52 Hz, 1H) 7.17 (d, J=8.20Hz, 1H) MS (ES+) m/z 374 [M+H]⁺.

Example 20wN-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chloro-3-methylpyridine-2-carboxamide

To a slurry of 5-chloro-3-methylpicolinic acid (37.6 mg, 0.22 mmol) in amixture of DCM/DMF/THF (2.0:2.0:0.5 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45.5 mg,0.24 mmol). The mixture containing the activated acid was stirred for 20min. under argon before it was added to a cold (0° C., external temp.)stirred solution of(1r,4r)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine(Example 20j, step 1, 57.0 mg, 0.18 mmol), hydrochloric acid (3 M) (0.3mL, 0.90 mmol) and triethylamine (0.099 mL, 0.71 mmol) in DMF (2.0 mL).After 2 h, another portion of activated acid, prepared as above, wasadded at 0° C. The mixture was stirred at 0° C. for 5 min. and then atr.t. for −1 h before raising the temperature to 30° C. for 30 min. Thereaction was quenched by addition of MeOH (1.5 mL) and the mixture wasconcentrated at reduced pressure to give a crude product that waspurified by preparative chromatography. The isolated material wastreated with 1.25M HCl in MeOH (1.5 mL) to give the title compound asthe hydrochloride salt (15 mg, 18% yield). ¹H NMR (500 MHz, CDCl₅) δ ppm1.14 (m, 1H), 1.28-1.44 (m, 3H), 1.64-1.78 (m, 2H), 1.96-2.10 (m, 2H),2.46 (s, 3H), 2.77 (s, 3H), 3.05-3.16 (m, 2H), 3.22 (m, 1H), 3.35 (s,3H), 7.32-7.36 (m, 2H), 7.62-7.66 (m, 2H), 8.37 (d, 1H), 10.05 (s, 1H);MS (ES+) m/z 466 [M+H]⁺.

Example 20xN-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-fluoropyridine-2-carboxamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (39.1 mg,0.20 mmol) was added to a suspension of 5-fluoropicolinic acid (26.6 mg,0.19 mmol) in DCM (0.5 mL). The solution was stirred for 10 min at r.t.and then dropwise added to an ice-cooled solution of4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine (Example 20j, step 1, 49 mg, 0.16 mmol) and 2M HCl (0.078 mL, 0.16mmol) in DMF (0.500 mL). The mixture was stirred at 0° C. for 1 h. Thesolvent was evaporated. The crude product was purified using preparativechromatography. The fractions containing the product were pooled and theMeOH was evaporated. DCM was added and the organic phase was extracted,dried through a phase separator and evaporated to give the titlecompound (25 mg, 37% yield): ¹H NMR (500 MHz, CD₃CN) δ ppm 0.99-1.10 (m,1H), 1.18-1.27 (m, 2H), 1.45 (td, 1H), 1.50-1.57 (m, 2H), 1.83-1.90 (m,2H), 2.20 (s, 3H), 2.94-3.06 (m, 2H), 3.06-3.15 (m, 1H), 3.25 (s, 3H),5.29 (br. s., 2H), 7.15 (d, 1H), 7.28 (d, 1H), 7.48 (dd, 1H), 7.72 (td,1H), 8.24 (dd, 1H), 8.52 (d, 1H), 9.78 (br. s., 1H); MS (ES+) m/z 436[M+H]⁺.

Example 20y(1r,4r)-4-Methoxy-5″-methyl-6′-[2-(prop-1-yn-1-yl)pyridin-4-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19, 75 mg, 0.20 mmol), potassium acetate (39.1 mg, 0.40 mmol),bis(pinacolato)diboron (55.7 mg, 0.22 mmol) and PdCl₂(dppf)-CH₂Cl₂adduct (8.14 mg, 9.97 μmol) were taken up in dioxane (2 mL) in amicrowave vial. The reaction vessel was sealed and heated at 110° C. for30 min and then at 120° C. for 15 min in a Biotage Initiator. Aftercooling, K₂CO₃ (55 mg, 0.40 mmol), Pd(Ph₃P)₄ (11.5 mg, 9.97 μmol), andwater (0.3 mL) were added followed by 4-bromo-2-(prop-1-ynyl)pyridine(Intermediate 33, 39 mg, 0.20 mmol) in dioxane (1 mL). The reactionvessel was sealed and heated at 110° C. for 30 min in a BiotageInitiator. After cooling, the mixture was filtered and concentrated invacuo. The product was purified by flash chromatography using a gradientof EtOAc in heptane (0-100%), then EtOAc:MeOH (9:1) followed bypreparative chromatography to give the title compound (7 mg, 9% yield):¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (m, 1H), 1.12-1.29 (m, 2H),1.39-1.50 (m, 3H), 1.83 (m, 2H), 2.08 (s, 3H), 2.18 (s, 3H), 2.90-3.13(m, 3H), 3.20 (s, 3H), 6.56 (s, 2H), 6.89 (d, 1H), 7.42 (d, 1H), 7.50(dd, 1H), 7.58 (d, 1H), 7.62 (dd, 1H), 8.49 (d, 1H); MS (MM-ES+APCI)+m/z 413 [M+H]⁺.

Example 20z(1r,4r)-4-Methoxy-5″-methyl-6′-[3-(prop-1-yn-1-yl)phenyl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

A mixture of sodium tetrachloropalladate(II) (2.9 mg, 9.70 μmol),3-(di-tert-butylphosphonium)propane sulfonate (5.2 mg, 20.0 μmop,(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19, 73 mg, 0.19 mmol) and 3-(prop-1-ynyl)phenylboronic acid(Intermediate 34, 47 mg, 0.29 mmol) in dioxane (2 mL) under argon washeated at reflux overnight. 3-(Prop-1-ynyl)phenylboronic acid (46.6 mg,0.29 mmol) was added and heating was continued for 4 h. The reactionmixture was partitioned between water and ethyl acetate, the organiclayer was dried over MgSO₄ and the solvent evaporated. The residue waspurified by preparative chromatography to give 4.0 mg (5% yield) of thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.91-1.02 (m, 1H),1.10-1.32 (m, 2H), 1.40-1.54 (m, 3H), 1.84 (d, 2H), 2.06 (s, 3H), 2.18(s, 3H), 2.92-3.13 (m, 3H), 3.21 (s, 3H), 6.55 (s, 2H), 6.75 (d, 1H),7.30-7.35 (m, 1H), 7.35-7.42 (m, 2H), 7.44-7.50 (m, 3H); MS(MM-ES+APCI)+ m/z 412 [M+H]⁺.

Example 20aa(1r,4r)-6′-(5-Bromopyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

A solution of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19, 130 mg, 0.35 mmol) in MeCN (3.5 mL) and DMF (0.5 mL) wasadded to a mixture of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (132 mg,0.52 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (14.1 mg, 0.02 mmol) and KOAc (136mg, 1.38 mmol) under argon atmosphere. The mixture was heated to 120° C.using MW for 30 min. PdCl₂(dppf)-CH₂Cl₂ adduct (14.1 mg, 0.02 mmol) and3,5-dibromopyridine (123 mg, 0.52 mmol) were added and the mixture washeated to 120° C. using MW for 30 min. 3,5-Dibromopyridine (123 mg, 0.52mmol), KOAc (35 mg, 0.35 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (14.1 mg, 0.02mmol) and water (100 μL) were added and the mixture was heated at 120°C. for 30 min. Another cycle of addition of 3,5-dibromopyridine andcatalyst and subsequent heating was conducted. The reaction mixture wasfiltered, the filtrate was concentrated and the residue was purified byflash chromatography using a gradient of EtOAc and heptane (0-100%) andthen MeON and DCM (0-5%). Further purification by preparativechromatography gave 22 mg of the title compound (14% yield). ¹H NMR (500MHz, DMSO-d₆) δ ppm 0.97 (td, 1H), 1.13-1.30 (m, 2H), 1.36-1.52 (m, 3H),1.83 (d, 2H), 2.17 (s, 3H), 2.91-2.98 (m, 1H), 3.00 (d, 1H), 3.09 (d,1H), 3.20 (s, 3H), 6.54 (s, 2H), 6.86 (d, 1H), 7.42 (d, 1H), 7.56 (dd,1H), 8.19 (t, 1H), 8.64 (d, 1H), 8.73 (d, 1H). MS (ES+) m/z 453 [M+H]⁺,and (ES−) m/z 451 [M−H]⁻.

Example 256′-Bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amineStep 1:N-(5-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-3(1H)-ylidene)-2-methylpropane-2-sulfinamide

Titanium(IV) ethoxide (2.119 mL, 10.14 mmol) was added to a solution of6-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-one(Intermediate 10, 1.14 g, 4.05 mmol) and 2-methyl-2-propanesulfinamide(0.688 g, 5.68 mmol) in 2-methyl-tetrahydrofuran (12 mL) and theresulting mixture was stirred at 70° C. overnight. When cooled to r.t.,MeOH (1.5 mL), sat. aq. NaHCO₃ (5 mL) and EtOAc (10 mL) were added. Themixture was stirred for 1 h, then filtered through diatomaceous earth.The filter cake was washed with EtOAc (3×10 mL). The combined organicswere washed with brine (30 mL), dried over MgSO₄, filtered, concentratedand purified on a silica gel column eluted with 0-40% EtOAc in heptaneto give 545 mg (35% yield) of the title compound; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.54 (br. s., 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 3.88 (dd,2H), 3.51 (m, 2H), 3.14 (s, 2H), 1.38 (m, 2H), 1.24 (m, 11H), MS (ES+)m/z 384 [M+H]⁺.

Step 2:6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-imine

HCl (4M in 1,4-dioxane) (0.683 mL, 2.73 mmol) was added to a solution ofN-(5-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-3(1H)-ylidene)-2-methylpropane-2-sulfinamide(Example 25 Step 1, 105 mg, 0.27 mmol) in anhydrous 1,4-dioxane (1 mL)and the resulting mixture was stirred under a nitrogen atmosphere atr.t. overnight. Et₂O (3 mL) was added, the precipitate was filtered off,washed with Et₂O and then dissolved in DCM (5 mL) and sat. aq. NaHCO₃ (5mL). The mixture was poured into a phase separator, the organic layerwas collected and concentrated to give the title compound that was usedin the next step without any further purification.

Step 3:6′-Bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4(3H)-thione

6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-imine(Example 25 Step 2, 235 mg, 0.84 mmol) and 2-oxopropanethioamide(Intermediate 2, 173 mg, 1.68 mmol) were taken up in anhydrous MeOH (5mL) and the resulting mixture was stirred at 60° C. under a nitrogenatmosphere for 3 h. When cooled to r.t. the mixture was concentrated andpurified on a silica gel column eluted with 0-50% EtOAc in heptane togive 385 mg (95% yield) of the title compound; ¹H NMR (500 MHz, DMSO-d₆)δ ppm 12.40 (br. s, 1H), 7.53 (dd, 1H), 7.36 (d, 1H), 7.03 (d, 1H), 3.71(td, 2H), 3.44 (m, 2H), 3.15 (m, 2H), 2.29 (s, 3H), 1.64 (s, 1H), 1.55(s, 1H), 1.27 (m, 2H); MS (ES+) m/z 365 [M+H]⁺.

Step 4:6′-Bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine

6′-Bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4(3H)-thione(Example 25 Step 3, 415 mg, 1.14 mmol) was taken up in NH₃ (7M in MeOH,13 mL, 91 mmol) and the resulting mixture was heated in a microwavereactor at 120° C. for 2×1 h. The to mixture was concentrated and theresulting residue was taken up in NH₃ (7M in MeOH, 13 mL, 91 mmol) andthen heated again for 1 h at 120° C. The mixture was concentrated andthe resulting residue was taken up in DCM (10 mL) and sat. aq. NaHCO₃ (5mL) and poured into a phase separator. The organic layer was collected,concentrated and purified on a silica gel column eluted with 0-10% (0.1MNH₃ in MeOH) in DCM to give 295 mg (75% yield) of the title compound: ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.36 (dd, 1H), 7.27 (d, 1H), 6.68 (d, 1H),6.65 (br. s, 1H), 3.65 (m, 2H), 3.46 (m, 1H), 3.38 (m, 1H), 3.15 (m,1H), 3.00 (m, 1H), 2.18 (s, 3H), 1.66 (td, 1H), 1.19 (m, 3H); MS (ES+)m/z 348[M+H]⁺.

Example 26a6′-(3-Chlorophenyl)-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine

A mixture of6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine(Example 25, 75 mg, 0.22 mmol), 3-chlorophenylboronic acid (40.4 mg,0.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride(8.86 mg, 10.77 μmol), 2 M aq. K₂CO₃ (0.215 mL, 0.43 mmol) and1,4-dioxane (2 mL) were mixed in a vial and heated in a microwavereactor at 130° C. for 15 min. When cooled to r.t., the mixture wasdiluted with brine (3 mL) and extracted with DCM (3×3 mL). The combinedorganics were concentrated and the resulting residue was purified bypreparative chromatography. The fractions containing the title compoundwere pooled, the solvent removed in vacuo, and the resulting aqueousresidue was extracted with DCM (3×3 mL). The combined organics werepassed through a phase separator and concentrated. The resulting residuewas taken up in MeOH (2 mL) and dried in a vacuum oven at 40° C. over aweekend to give 36 mg (44% yield) of the title compound; ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.55 (t, 1H), 7.49 (m, 2H), 7.39 (m, 3H), 6.80 (d,1H), 6.61 (br. s, 1H), 3.66 (m, 2H), 3.48 (m, 1H), 3.40 (td, 1H), 3.22(d, 1H), 3.08 (d, 1H), 2.19 (s, 3H), 1.72 (td, 1H), 1.22 (m, 3H); MS(ES+) m/z 380 [M+H]⁺.

Example 26c6′-(3-Chloro-4-fluorophenyl)-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine

The title compound was synthesized as described for Example 26a in 42%yield, starting from6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine(Example 25, 75 mg, 0.22 mmol) and 3-chloro-4-fluorobenzeneboronic acid(45.1 mg, 0.26 mmol); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.72 (dd, 1H),7.52 (m, 2H), 7.42 (m, 2H), 6.80 (d, 1H), 6.60 (br. s, 1H), 3.66 (m,2H), 3.48 (t, 1H), 3.40 (m, 1H), 3.20 (m, 1H), 3.07 (m, 1H), 2.19 (s,3H), 1.71 (td, 1H), 1.23 (m, 3H); MS (ES+) m/z 398 [M+H]⁺.

Example 276′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-(5′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 11, 819 mg, 2.60 mmol), 2-methylpropane-2-sulfinamide (630mg, 5.20 mmol) and titanium ethoxide (1.874 mL, 9.10 mmol) weredissolved in 2-Me THF (9 mL) and heated to 120° C. with MW for 1 h.EtOAc (20 mL) and NaHCO₃ (aq., sat, 2 mL) were added under stirring. Themixture was left to stand without stirring for 1 h. The organic phasewas collected by filtration, dried over MgSO₄ and concentrated. Flashchromatography with a gradient of 0-50% EtOAc in n-heptane gave thetitle compound (340 mg, 31% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.25(s, 9H), 1.56-1.71 (m, 2H), 2.10 (br. s., 6H), 3.12 (s, 2H), 7.49 (d,1H), 7.81 (dd, 1H), 8.43-8.63 (m, 1H). MS (ES+) m/z 418 [M+H]⁺.

Step 2: 6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4M in 1,4-dioxane, 3.38 mL, 13.51 mmol) was added to a solution ofN-(5′-bromo-4,4-difluorospiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 27 Step 1, 565 mg, 1.35 mmol) in anhydrous 1,4-dioxane (4 mL).The resulting mixture was stirred under a nitrogen atmosphere at r.t.for 90 min. Et₂O (2 mL) was added and the precipitate was filtered offand washed with Et₂O. The solid was partitioned between DCM (8 mL) andsat. aq. NaHCO₃ (8 mL). The phases were separated and the organic layerwas dried over MgSO₄ and concentrated to give6′-bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (418mg, 99% yield), that was used directly in the next step. MS (ES+) m/z314 [M+H]⁺.

Step 3:6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 27 Step 2, 418 mg, 1.33 mmol) and 2-oxopropanethioamide(Intermediate 2, 412 mg, 3.99 mmol) were dissolved in dry MeOH (6 mL)and the resulting solution was heated at 60° C. under N₂(g) overnight.The reaction mixture was allowed to cool to r.t. A precipitate formedwhich was filtered off and dried in vacuo, yielding the title compound(387 mg, 73% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29-1.47 (m, 2H),1.49-1.62 (m, 2H), 1.81-2.08 (m, 4H), 2.28 (s, 3H), 3.09 (d, 1H), 3.15(d, 1H), 7.02 (d, 1H), 7.33 (d, 1H), 7.53 (d, 1H), 12.42 (s, 1H); MS(ES+) m/z 399.0 [M+H]^(|).

Step 4:6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 27 Step 3, 57 mg, 0.14 mmol) in ammonia (7 M in MeOH) (1.5 mL,10.5 mmol) was heated in a microwave reactor for 40 min at 100° C. Themixture was concentrated, re-dissolved in ammonia (7 M in MeOH) (1.5 mL,10.5 mmol) and heated with MW for 40 min at 100° C. The mixture wasconcentrated. Purification of the crude product by flash chromatographyusing a gradient of CHCl₃/MeOH 40:1-30:1-20:1 gave the title compound(21 mg, 39% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.15-1.29 (m, 1H),1.47 (m, 2H), 1.61-1.73 (m, 1H), 1.73-1.97 (m, 4H), 2.18 (s, 3H), 2.98(d, 1H), 3.08 (d, 1H), 6.67 (m, 3H), 7.26 (d, 1H), 7.37 (dd, 1H); MS(ES+) m/z 382 [M+H]⁺.

Example 28c6′-(5-Chloropyridin-3-yl)-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

Sodium tetrachloropalladate(II) (7.70 mg, 0.03 mmol),3-(di-tert-butylphosphonium)propane sulfonate (7.02 mg, 0.03 mmol),6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 27, 100 mg, 0.26 mmol) and 5-chloropyridin-3-ylboronic acid(52.0 mg, 0.31 mmol) were added to a microwave vial and dissolved in2-methyl-tetrahydrofuran (1 mL). K₂CO₃ (2M aq) (0.392 mL, 0.78 mmol) wasadded and the vial was flushed with Ar (g) and capped. The mixture washeated in a microwave reactor at 100° C. for 45 min. Additional sodiumtetrachloropalladate(II) (7.70 mg, 0.03 mmol),3-(di-tert-butylphosphonium)propane sulfonate (7.02 mg, 0.03 mmol) and0.5 equiv. 5-chloropyridin-3-ylboronic acid was added to the reactionmixture and it was heated to 90° C. for 1 h. Water was added and theresidue was extracted with EtOAc (×3). The organic phases were driedwith MgSO₄ and concentrated. The crude product was purified on a silicagel column (4 g SiO₂, 7 M NH₃ in MeOH in DCM 1:9/DCM 0-100%) to give thetitle compound (41 mg, 38% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.23-1.32 (m, 1H), 1.52 (br. s., 2H), 1.72 (br. s., 1H), 1.79-1.98 (m,4H), 2.19 (s, 3H), 3.08 (d, 1H), 3.16 (d, 1H), 6.62 (br. s., 2H), 6.90(d, 1H), 7.43 (d, 1H), 7.60 (dd, 1H), 8.10 (t, 1H), 8.57 (d, 1H), 8.72(d, 1H). MS (APCI+) m/z 415.2 [M+H]⁺.

Example 28dN-(4″-Amino-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloropyridine-2-carboxamideStep 1:4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine

6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 27, 116 mg, 0.30 mmol), trans-4-hydroxy-L-proline (40 mg, 0.30mmol), copper(I) iodide (29 mg, 0.15 mmol) and K₂CO₃ (126 mg, 0.91 mmol)were mixed in dry dimethylsulfoxide (3 mL) in a microwave vial. Themixture was stirred under argon at r.t. for 30 min. Ammonia (30-33% inH₂O) (0.285 mL, 4.55 mmol) was added, the vial was sealed and heated at110° C. for 3 h in a microwave synthesizer. Additional copper(I) iodide(29 mg, 0.15 mmol) and trans-4-hydroxy-L-proline (40 mg, 0.30 mmol) wereadded and the mixture was then heated to 110° C. for 4 h. The mixturewas diluted with EtOAc (10 mL) and washed with brine (10 mL). Theaqueous layer was extracted with EtOAc (2×10 mL). The organic layerswere combined and concentrated in vacuo. The residue was applied on ashort column of silica (4 g SiO₂) and eluted with 0-100% (7 M NH₃ inMeOH and DCM 1:9) in DCM to give the title compound (46 mg, 48% yield):¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 (t, 1H), 1.48 (br. s., 2H),1.64-1.96 (m, 5H), 2.11-2.17 (m, 3H), 2.83 (d, 1H), 2.90 (d, 1H), 4.75(s, 2H), 5.83 (d, 1H), 6.37 (dd, 1H), 6.50 (s, 2H), 6.90 (d, 1H); MS(ES+) m/z 319.1 [M+H]⁺.

Step 2:N-(4″-Amino-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chloropyridine-2-carboxamide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (36 mg,0.19 mmol) was added to a suspension of 5-chloropicolinic acid (27 mg,0.17 mmol) in DCM (0.5 mL). The obtained orange solution was stirred for5 min and then added dropwise over 2 min to an ice-cooled solution of4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine(Example 28d Step 1, 46 mg, 0.14 mmol) and 2M aq. HCl (0.072 nit, 0.14mmol) in DMF (0.5 mL). The mixture was stirred at 0° C. for 10 min andwas then allowed to reach r.t. overnight. The solvent was evaporated.The crude was purified using preparative chromatography to give thetitle compound (11 mg, 17% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.23(d, 1H), 1.51 (d, 2H), 1.66-1.98 (m, 5H), 2.18 (s, 3H), 2.99 (d, 1H),3.08 (d, 1H), 6.63 (br. s., 1H), 7.23-7.29 (m, 2H), 7.62 (d, 1H), 8.10(d, 1H), 8.18 (dd, 1H), 8.74 (s, 1H), 10.50 (s, 1H); MS (APCI+) m/z458.1 [M+H]⁺.

Example 28h4,4-Difluoro-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (26 mg, 24% yield) was prepared as described forExample 28c starting from6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 27, 100 mg, 0.26 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronicacid (Intermediate 15, 50.5 mg, 0.31 mmol). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.22-1.30 (m, 1H), 1.51 (br. s., 2H), 1.71 (br. s., 1H), 1.78-1.97(m, 4H), 2.09 (s, 3H), 2.19 (s, 3H), 3.06 (d, 1H), 3.15 (d, 1H), 6.61(s, 2H), 6.85 (d, 1H), 7.41 (d, 1H), 7.56 (dd, 1H), 7.91 (t, 1H), 8.51(d, 1H), 8.67 (d, 1H). MS (APCI+) m/z 419.2 [M+H]⁺.

Example 295′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amineStep 1:N-(5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexane]-3-ylidene)-2-methylpropane-2-sulfinamide

To a mixture of5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-one(Intermediate 12, 2.8 g, 9.00 mmol) and 2-methylpropane-2-sulfinamide(2.024 g, 16.20 mmol) in methyl THF (15 mL) was added titanium ethoxide(3.71 mL, 18.00 mmol) and the reaction was heated to reflux. After 21 hthe reaction was allowed to cool to r.t. whereafter it was diluted withEtOAc (150 mL). Water (12 mL) was added dropwise over 10 min undervigorous stirring and then the mixture was left standing withoutstirring for 1.5 h. The solids were filtered off and the organics wereevaporated. The crude product was purified by flash chromatography usinga gradient of 0%-50% EtOAc in heptane, yielding 2.41 g of the titlecompound (65% yield): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.33 (s, 9H), 1.81(m, 6H), 2.12 (d, 2H), 3.33 (m, 1H), 3.42 (s, 3H), 6.94 (d, 1H), 7.59(dd, 1H), 8.53 (m, 1H); MS (ES+) m/z 415 [M+H]⁺.

Step 2: 5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-imine

To a solution ofN-(5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexane]-3-ylidene)-2-methylpropane-2-sulfinamide(Example 29 Step 1, 2 g, 4.83 mmol) in anhydrous 1,4-dioxane (40 mL) wasadded 4M HCl in 1,4-dioxane (12.07 mL, 48.27 mmol) and the resultingmixture was stirred under a nitrogen atmosphere at rt overnight. Et₂O(30 mL) was added and the precipitate was filtered off and washed withEt₂O, then partitioned between DCM (40 mL) and sat. aq. NaHCO₃ (40 mL).The phases were separated and the organic layer concentrated, yielding1.37 g of the crude title compound which was used immediately in thenext step: MS (EI) m/z 309 M⁺.

Step 3:5′-Bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazole]-4″(3″H)-thione

5-Bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexan]-3-imine (Example29 Step 2, 1.37 g, 4.41 mmol) and 2-oxopropanethioamide (Intermediate 2,0.909 g, 8.81 mmol) were dissolved in dry MeOH (25 mL) and the resultingorange solution was heated at 60° C. under a nitrogen atmosphereovernight. More 2-oxopropanethioamide (400 mg) was added and stirringcontinued. After 24 h the mixture was allowed to cool to r.t. and thesolvent was evaporated. Purification by flash chromatography using agradient of 0-100% EtOAc in heptane afforded 373 mg of the titlecompound (21% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35 (m, 1H), 1.47(m, 3H), 1.87 (m, 2H), 1.97 (m, 2H), 2.29 (s, 3H), 3.13 (s, 3H), 4.11(m, 1H), 6.99 (d, 1H), 7.16 (d, 1H), 7.48 (dd, 1H); MS (ES+) m/z 396[M+H]⁺.

Step 4:5′-Bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine

A mixture of5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazole]-4″(3″H)-thione(Example 29 Step 3, 365 mg, 0.92 mmol) and 7M ammonia in MeOH (10 mL,70.00 mmol) was prepared in a microwave vial. The vial was sealed andthe reaction was heated at 120° C. for 30 min in a microwave reactor.The mixture was concentrated and the residue was dissolved in 7M ammoniain McOH (4 mL) and heated once more at 120° C. for 30 min using MW.Again, the mixture was concentrated, 7M ammonia in MeOH (10 mL, 70.00mmol) was added and the mixture was heated at 120° C. The mixture wasconcentrated and the crude product was dissolved in 20% MeOH in DCM andfiltered through a silica pad and eluted with 20% MeOH in DCM. Afterconcentration of the organic layer, DCM was added to the residue. Asolid was formed which was filtered off and washed with DCM, yielding 94mg of the title compound (27% yield). The mother liquor wasconcentrated, Et₂O was added and the solid was filtered off and dried,yielding a second crop of the title compound (85 mg, 24% yield). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.19 (d, 1H), 1.43 (m, 3H), 1.80 (d, 2H), 1.95(m, 2H), 2.20 (s, 3H), 3.07 (d, 1H), 3.21 (s, 3H), 6.68 (d, 1H), 6.74(br. s., 2H), 6.87 (d, 1H), 7.31 (dd, 1H); MS (ES+) m/z 379 [M+H]^(|).

Example 30b5′-(3-Chlorophenyl)-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine

3-Chlorophenylboronic acid (47.7 mg, 0.31 mmol),5′-bromo-4-methoxy-5″-methyldispiro-[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine(Example 29, 77 mg, 0.20 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (8.37 mg,10.18 μmol) were put in a microwave vial and dissolved in dry dioxane (2mL). A 2M aq. solution of K₂CO₃ (0.204 mL, 0.41 mmol) was added, themixture was degassed with nitrogen gas and the mixture was heated at120° C. for 20 min in a microwave reactor. The mixture was combined witha second reaction from 10 mg (0.03 mmol) of5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amineand concentrated. EtOAc (7 mL) and a sat. aq. solution of NaHCO₃ (5 mL)was added and the phases were separated. The aqueous phase was extractedwith EtOAc (5 mL) and the combined organic layers were dried over MgSO₄,filtered and evaporated. The crude product was purified by preparativechromatography, yielding 38.5 mg of the title compound (41% yield). ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.21 (m, 1H), 1.46 (m, 3H), 1.82 (m, 2H),1.98 (m, 2H), 2.21 (s, 3H), 3.09 (m, 1H), 3.22 (s, 3H), 6.71 (br. s.,2H), 6.85 (d, 1H), 6.98 (d, 1H), 7.32 (m, 1H), 7.40 (s, 1H), 7.47 (m,1H), 7.51 (m, 1H), 7.54 (s, 1H); MS (APCI+) m/z 410 [M+H]⁺.

Example 30d5′-(5-Chloropyridin-3-yl)-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine

Sodium tetrachloropalladate (II) (2.294 mg, 7.80 μmol),3-(di-text-butylphosphonium)propane sulfonate (4.19 mg, 0.02 mmol),5-chloropyridin-3-ylboronic acid (25.8 mg, 0.16 mmol) and5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine(Example 29, 59 mg, 0.16 mmol), was added to a vial.2-Methyl-tetrahydrofuran (1 mL) and 2 M aq. K₂CO₃ (0.234 mL, 0.47 mmol)was added and the mixture was degassed by bubbling nitrogen gas throughthe solution. The vial was sealed and heated in a microwave reactor at90° C. for 30 min and the crude mixture was combined with a secondreaction from 20 mg (0.05 mmol) of5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine.Water (5 mL) and EtOAc (5 mL) was added and the phases were separated.The aqueous phase was extracted with EtOAc (5 mL) and the combinedorganic layers were dried over MgSO₄, filtered and evaporated.Purification by flash chromatography using a 0-10% gradient of MeOH,containing 1.2% 7M NH₃ in MeOH, in DCM afforded 36 mg of the titlecompound (56% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.22 (m, 1H), 1.46(m, 3H), 1.81 (m, 2H), 1.97 (m, 2H), 2.21 (s, 3H), 3.10 (m, 1H), 3.22(s, 3H), 6.71 (br. s., 2H), 7.01 (m, 2H), 7.61 (dd, 1H), 8.08 (t, 1H),8.51 (d, 1H), 8.72 (d, 1H); MS (APCI+) m/z 411 [M+H]⁺.

Example 30e4-Methoxy-5″-methyl-5′-[5-(prop-1-yn-1-yl)pyridin-3-yl]dispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine

5-(Prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 57.4 mg, 0.36mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II)(9.79 mg, 0.01 mmol), cesium carbonate (233 mg, 0.71 mmol) and5′-bromo-4-methoxy-5″-methyldispiro[cyclohexane-1,2′-[1]benzofuran-3′,2″-imidazol]-4″-amine(Example 29, 90 mg, 0.24 mmol) were dissolved in a 6:3:1 mixture ofDME:EtOH:water (2 mL) and heated at 150° C. in a microwave reactor for15 min. The mixture was concentrated and the residue was partitionedbetween EtOAc (7 mL) and sat. aq. NaHCO₃ (5 mL). The layers wereseparated and the organic layer was dried over MgSO₄ and concentrated.Purification of the crude product by preparative chromatography afforded41 mg of the title compound (42% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.22 (m, 1H), 1.46 (m, 3H), 1.81 (m, 2H), 1.98 (m, 2H), 2.09 (s, 3H),2.21 (s, 3H), 3.10 (m, 1H), 3.22 (s, 3H), 6.70 (s, 2H), 6.95 (d, 1H),6.99 (d, 1H), 7.56 (d, 1H), 7.91 (t, 1H), 8.47 (d, 1H), 8.67 (d, 1H); MS(APCI+) m/z 415 [M+H]⁺.

Example 456′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amineStep 1:N-(6-Bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-ylidene)-2-methylpropane-2-sulfinamide

6-Bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-one(Intermediate 26, 2.007 g, 6.75 mmol), 2-methylpropane-2-sulfinamide(1.228 g, 10.13 mmol) and titanium ethoxide (2.78 mL, 13.51 mmol) weredissolved in methyl THF (16 mL) and heated to reflux for 19 h. Thereaction was left to cool down to r.t. when EtOAc (80 mL) and NaHCO₃(sat., 5 mL) were added under stirring. The mixture was let standing for1 h. The organic phase was collected by filtration, dried over MgSO₄ andconcentrated. The crude product was purified by flash chromatographyusing a gradient of 0-50% EtOAc in heptane. The desired fractions wereevaporated to give the title compound as a mixture of diastereomers in aratio 1:1 as determined by NMR (2.63 g, 97% yield): ¹H NMR (500 MHz,CDCl₃) δ ppm 1.34 (s, 9H), 1.50-1.57 (m, 0.5H), 1.60-1.68 (m, 1H), 1.73(m, 0.5H) 1.87-2.09 (m, 2H), 2.99 (d, 0.5H), 3.26 (d, 0.5H), 3.33 (d,0.5H), 3.45-3.61 (m, 2H), 3.64 (d, 0.5H), 3.77-3.93 (m, 2H), 6.88-6.93(m, 1H), 7.48 (dd, 1H), 7.98 (dd, 1H); MS (ES+) m/z 401.9 [M+H]⁺.

Step 2: 6-Bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-imine

HCl (4 M in 1,4-dioxane) (0.395 mL, 12.99 mmol) was added to asuspension ofN-(6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-ylidene)-2-methylpropane-2-sulfinamide(Example 45 Step 1, 520 mg, 1.30 mmol) in anhydrous 1,4-dioxane (6 mL)and the resulting mixture was stirred under a nitrogen atmosphere atr.t. for 2 days. A precipitate was formed. The precipitate was filteredoff and washed with Et₂O. The solid was then dissolved in DCM and sat.aq. NaHCO₃. The mixture was poured into a phase separator, the organiclayer was collected and concentrated. The title compound was useddirectly in the next step without any further purification.

Step 3:6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4(3H)-thione

2-Oxopropanethioamide (Intermediate 2, 289 mg, 2.80 mmol) and6-bromo-5′,6′-dihydro-4′H-spiro[chromene-2,3′-pyran]-4(3H)-imine(Example 45 Step 2, 331.4 mg, 1.12 mmol) were dissolved in acetonitrile(3 mL) and heated using MW for 20 min to 120° C. The solvent wasevaporated under reduced pressure. The crude product was purified byflash chromatography using a gradient of 0-50% EtOAc in heptane butco-eluted with byproducts. The not completely pure product was used as amixture in the next step.

Step 4:6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine

6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4(3H)-thione(Example 45 Step 3, 319 mg, 0.84 mmol) was taken up in ammonia (7M inMeOH, 10 mL, 70.00 mmol) and the resulting mixture was heated in themicrowave reactor at 120° C. for 2 h. The solvent was evaporated andammonia (7M in MeOH, 10 mL, 70.00 mmol) was added and the reaction washeated using MW for 1 h at 120° C. The solvent was evaporated and theresulting residue was taken up in DCM and saturated NaHCO₃ and pouredinto a phase separator. The organic phase was dried and concentrated.The crude product was purified by flash chromatography using a gradientof 0-100% EtOAc in heptane followed by a gradient of 0-40% MeOH with 1%NH₃ in DCM. The desired fractions were evaporated to give the titlecompound (130 mg, 43% yield) as a mixture of diastereomers in a 1:1ratio as determined by NMR: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41-1.49(m), 1.76-1.89 (m), 1.89-1.95 (m), 1.95-2.06 (m), 2.21 (s), 2.23 (s),3.16 (m), 3.41 (d), 3.51 (dd), 3.69 (dd), 3.92 (t), 4.07-4.12 (m), 6.45(d), 6.47 (d), 6.57 (br. s.), 6.61 (br. s.), 6.82 (d), 7.25 (d), 7.26(d); MS (ES+) m/z 366.0 [M+H]⁺.

Separation of the isomers of6′-bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine

The diastereomeric mixture of6′-bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine(Example 45 Step 4) was separated (3 separate injections) usingpreparative chromatography (Gilson Prep. system with a XBridge C18 10 μm50×250 mm column applying a gradient of 15-55% B (100% MeCN) in A (95%0.05 M NH₄OAc in MilliQ water and 5% MeCN) over 15 min at a flow rate of100 mL/min) to give:

Isomer 1 (0.143 g, 11.5% yield) with undetermined absolute configurationand with retention time 12.5 min: ¹H NMR (500 MHz, CDCl₃) δ ppm1.54-1.61 (m, 1H), 1.84 (ddd, 2H), 1.96-2.06 (m, 1H), 2.13-2.18 (m, 1H),2.36 (s, 3H), 3.57 (ddd, 1H), 3.70 (d, 1H), 3.80-3.86 (m, 1H), 4.03 (d,1H), 6.60 (d, 1H), 6.88 (d, 1H), 7.25 (dd, 1H); MS (ES+) m/z 366.0[M+H]⁺.

Isomer 2 (0.109 g, 9% yield) with undetermined absolute configurationand with retention time 13.1 min: ¹H NMR (500 MHz, CDCl₃) δ ppm1.52-1.60 (m, 1H), 1.72 (br. s., 2H), 1.86 (ddd, 1H), 1.95-2.06 (m, 1H),2.20-2.26 (m, 1H), 2.37 (s, 3H), 3.57 (ddd, 1H), 3.66 (d, 1H), 3.80-3.86(m, 1H), 3.95 (d, 1H), 6.59 (d, 1H), 6.88 (d, 1H), 7.25 (dd, 1H); MS(ES+) m/z 366.0 [M+H]⁺.

Example 46a6′-(3-Chlorophenyl)-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine

Isomer 1

A mixture of6′-bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine(Example 45 Isomer 1, 116 mg, 0.32 mmol), 3-chlorophenylboronic acid(64.7 mg, 0.41 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (26.0 mg,0.03 mmol), K₂CO₃ (2 M aq) (0.318 mL, 0.64 mmol) and 1,4-dioxane (2 mL)were added to a microwave vial. The vial was capped, evacuated andfilled with argon. The vial was heated in a microwave reactor at 130° C.for 20 min. Brine was added and the residue was extracted with DCM (×3),dried with a phase separator and concentrated under reduced pressure.The crude product was purified by preparative chromatography. Thedesired fractions were concentrated. Water and DCM were added and thelayers separated. The organic phase was dried with a phase separator andconcentrated to give isomer 1 of the title compound (38.5 mg, 30% yield)with undetermined configuration: ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.44-1.53 (m, 1H), 1.83-1.92 (m, 3H), 2.01 (d, 2H), 2.22 (s, 3H),3.41-3.48 (m, 1H), 3.56 (d, 1H), 3.67-3.73 (m, 1H), 3.99 (d, 1H), 6.58(s, 1H), 6.62 (s, 1H), 6.95 (d, 1H), 7.31-7.39 (m, 2H), 7.39-7.47 (m,3H); MS (ES+) m/z 396 [M+H]⁺.

Isomer 2

6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine(Example 45 Isomer 2, 102 mg, 0.28 mmol) was treated as described forExample 46a, Isomer 1, to give isomer 2 of the title compound (52 mg,46% yield) with undetermined configuration: ¹H NMR (500 MHz, DMSO-d₆) δppm 1.45-1.51 (m, 1H), 1.80-1.91 (m, 3H), 2.04 (d, 1H), 2.06-2.11 (m,1H), 2.25 (s, 3H), 3.40-3.47 (m, 1H), 3.54 (d, 1H), 3.68-3.74 (m, 1H),3.94 (d, 1H), 6.54 (s, 1H), 6.59 (d, 1H), 6.95 (d, 1H), 7.32-7.36 (m,1H), 7.36-7.40 (m, 1H), 7.41 (d, 1H), 7.43-7.47 (m, 2H); MS (ES+) m/z396 [M+H]⁺.

Example 46b6′-(3-Chloro-4-fluorophenyl)-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine

Isomer 1

6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine(Example 45 Isomer 1, 77 mg, 0.21 mmol) and3-chloro-4-fluorophenylboronic acid (47.9 mg, 0.27 mmol) were reactedusing the conditions described for Example 46a Isomer 1, to give Isomer1 of the title compound (33 mg, 38% yield) with undeterminedconfiguration: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.44-1.52 (m, 1H),1.81-1.92 (m, 3H), 1.97-2.05 (m, 2H), 2.22 (s, 3H), 3.41-3.48 (m, 1H),3.56 (d, 1H), 3.67-3.74 (m, 1H), 3.98 (d, 1H), 6.57 (s, 2H), 6.60 (d,1H), 6.94 (d, 1H), 7.38-7.46 (m, 3H), 7.60 (dd, 1H); MS (ES+) m/z 414[M+H]⁺.

Isomer 2

6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine(Example 45 Isomer 2, 77 mg, 0.21 mmol), and3-chloro-4-fluorophenylboronic acid (47.9 mg, 0.27 mmol) was reactedusing the conditions described for Example 46a Isomer 1, to give Isomer2 of the title compound, (24 mg, 27% yield) with undeterminedconfiguration: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41-1.54 (m, 1H),1.78-1.92 (m, 3H), 1.99-2.13 (m, 2H), 2.25 (s, 3H), 3.40-3.47 (m, 1H),3.54 (d, 1H), 3.68-3.74 (m, 1H), 3.94 (d, 1H), 6.53 (br. s, 2H), 6.58(d, 1H), 6.94 (d, 1H), 7.39-7.46 (m, 3H), 7.58-7.63 (m, 1H); MS (ES+)m/z 414 [M+H]⁺.

Example 476-Bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chromane-4,2′-imidazole]-4′-amineStep 1:N-(6-Bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)-2-methylpropane-2-sulfinamide

6-Bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (Intermediate 27, 1.5g, 4.82 mmol) and 2-methylpropane-2-sulfinamide (1.052 g, 8.68 mmol)were dissolved in dry 2-methyl-tetrahydrofuran (12 mL). Neat titaniumethoxide (1.788 mL, 8.68 mmol) was added. The resulting mixture washeated by MW at 130° C. for 60 min. The mixture was diluted with EtOAc(150 mL) and water (40 mL) was added dropwise during vigorous stirringof the reaction mixture. The stirring was continued for 15 min. Thesolid was decanted and the mixture filtered through a pad ofdiatomaceous earth. The organic layer was separated, dried over MgSO₄and vacuum filtered directly through a pad of silica (approx. 10 g) andconcentrated in vacuo to give the title compound (1.8 g, 90% yield). MS(ES+) m/z 414 [M+H]⁺.

Step 2:6-Bromo-4′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazole]-5′(1′H)-thione

N-(6-Bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)-2-methylpropane-2-sulfinamide(Example 47 Step 1, 0.5 g, 1.21 mmol) and 2-oxopropanethioamide(Intermediate 2, 0.373 g, 3.62 mmol) were dissolved in dry acetonitrile(4.0 mL) in a dry microwave vial. The vial was sealed and heated with MWfor 20 min. at 130° C. The solvent was evaporated to give the crudetitle compound that was used directly in the next reaction. MS (ES+) m/z395 [M+H]⁺.

Step 3:6-Bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-4′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazole]-5′(1′H)-thione(Example 47 Step 2, 3.78 g, 9.56 mmol) was dissolved in 7N solution ofammonia in MeOH (30.1 mL, 210 mmol) and heated with MW at 100° C. for 1hr. The reaction mixture was concentrated, the residue re-dissolved inDCM, washed with brine, dried over Na₂SO₄ and concentrated at reducedpressure. Two isomeric mixtures were separated using a Gilson RPHPLCsystem with a X-Bridge C18, 50×250 mm column with gradient elutionof acetonitrile in 0.05 M aq. ammonium acetate to give:

Isomeric mixture 1 (241 mg, 7% yield) with retention time 13.75 min: MS(ES+) m/z 378 [M+H]⁺, andIsomeric mixture 2 (206 mg, 6% yield) with retention time 14.53 min: MS(ES+) m/z 378 [M+H]⁺.

Step 4: Separation of the isomers of6-bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine

The isomers in Isomeric mixture 1 from Example 47 Step 3, 60 mg, wereseparated on chiral SFC using a Chiralcel OD-H; 4.6*250 mm; 5 μm columnand a mobile phase consisting of 10% MeOH (containing 0.1% diethylamine)and 90% CO₂ at a flow rate of 3 mL/min to give the followingstereoisomers of undetermined absolute configuration:

Isomer 1 (13.7 mg, 11% yield) with retention time 7.63 min: ¹H NMR (400MHz, CDCl₃) δ ppm 1.48 (m, 2H), 1.66 (m, 2H), 1.83 (dt, 1H), 1.98 (ddt,1H), 2.41 (s, 3H), 2.48 (m, 1H), 3.38 (m, 2H), 3.92 (d, 1H), 4.25 (m,1H), 4.33 (ddd, 1H), 6.55 (d, 1H), 6.79 (d, 1H), 7.22 (dd, 1H); MS (ES+)m/z 378 [M+H]⁺.

Isomer 2 (15.7 mg, 13% yield) with retention time 8.67 min: ¹H NMR (500MHz, CDCl₃) δ ppm 1.46 (m, 1H), 1.53 (dd, 1H), 1.67 (m, 2H), 1.83 (dt,1H), 1.99 (dtd, 1H), 2.44 (s, 3H), 2.50 (m, 1H), 3.38 (m, 2H), 3.92 (d,1H), 4.25 (dd, 1H), 4.32 (ddd, 1H), 6.56 (d, 1H), 6.79 (d, 1H), 7.24(dd, 1H); MS (ES+) m/z 378 [M+H]⁺.

Isomer 3 (7.6 mg, 6% yield) with retention time 10.60 min: ¹H NMR (500MHz, CDCl₃) δ ppm 1.46 (m, 1H), 1.56 (dd, 1H), 1.67 (m, 2H), 1.83 (dt,1H), 1.97 (dtd, 1H), 2.35 (s, 3H), 2.40 (t, 1H), 3.38 (m, 2H), 3.93 (d,1H), 4.26 (dd, 1H), 4.47 (ddd, 1H), 6.72 (d, 1H), 6.79 (d, 1H), 7.24(dd, 1H); MS (ES+) m/z 378 [M+H]⁺.

Isomer 4 (7.8 mg, 6.5% yield) with retention time 11.64 min: ¹H NMR (500MHz, CDCl₃) δ ppm 1.45 (m, 1H), 1.55 (dd, 1H), 1.67 (m, 2H), 1.83 (dt,1H), 1.97 (dtd, 1H), 2.34 (s, 3H), 2.40 (m, 1H), 3.38 (m, 2H), 3.93 (d,1H), 4.26 (dd, 1H), 4.47 (ddd, 1H), 6.71 (d, 1H), 6.79 (d, 1H), 7.24(dd, 1H); MS (ES+) m/z 378 [M+H]⁺.

The isomers in Isomeric mixture 2 from Example 47 Step 3, 60 mg, wereseparated on chiral SFC using a Chiralpak AD-H; 20*250 mm; 5 μm column;and a mobile phase consisting of 15% IPA (containing 0.1% diethylamine)and 85% CO₂ at a flow rate of 50 mL/min to give the followingstereoisomers of undetermined absolute configuration:

Isomer 5 (14.2 mg, 11% yield) with retention time 5.49 min: ¹H NMR (500MHz, CDCl₃) δ ppm 1.44 (d, 1H), 1.66 (m, 3H), 1.98 (m, 2H), 2.43 (s,3H), 2.57 (m, 1H), 3.45 (m, 2H), 3.92 (m, 2H), 4.41 (m, 1H), 6.57 (d,1H), 6.80 (d, 1H), 7.24 (dd, 1H); MS (ES+) m/z 378 [M+H]⁺.

Isomer 6 (4.4 mg, 4% yield) with retention time 6.27 min: ¹H NMR (500MHz, CDCl₃) δ ppm 1.49 (d, 1H), 1.64 (m, 3H), 1.97 (m, 2H), 2.39 (s,3H), 2.48 (m, 1H), 3.43 (m, 2H), 3.93 (m, 2H), 4.53 (ddd, 1H), 6.74 (d,1H), 6.80 (m, 1H), 7.25 (m, 1H); MS (ES+) m/z 378 [M+H]⁺.

Isomer 7 (14.3 mg, 12% yield) with retention time 7.17 min: ¹H NMR (500MHz, CDCl₃) δ ppm 1.44 (d, 1H), 1.66 (m, 3H), 1.99 (m, 2H), 2.43 (s,3H), 2.57 (m, 1H), 3.45 (m, 2H), 3.93 (m, 2H), 4.41 (m, 1H), 6.57 (d,1H), 6.80 (d, 1H), 7.24 (dd, 1H); MS (ES+) m/z 378 [M+H]⁺.

Isomer 8 (4.5 mg; 4% yield) with retention time 8.98 min: ¹H NMR (500MHz, CDCl₃) δ ppm 1.43 (m, 1H), 1.63 (m, 3H), 1.94 (m, 1H), 2.04 (m,1H), 2.31 (m, 3H), 2.47 (t, 1H), 3.43 (m, 2H), 3.94 (m, 2H), 4.53 (m,1H), 6.71 (d, 1H), 6.78 (d, 1H), 7.23 (dd, 1H); MS (ES+) m/z 378 [M+H]⁺.

Example 48a6-(3-Chlorophenyl)-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine

A mixture of6-bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine(Isomeric mixture 1 from Example 47 Step 3, 0.181 g, 0.48 mmol),3-chlorophenylboronic acid (0.112 g, 0.72 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.035 g,0.04 mmol), K₂CO₃ (2 M aq.) (0.479 mL, 0.96 mmol) and 1,4-dioxane (4 mL)were mixed in a vial and heated in a microwave reactor at 130° C. for 15min. When cooled to r.t. the mixture was diluted with brine (3 mL) andextracted with DCM (3×3 mL). The combined organics were concentrated andthe resulting residue was taken up in MeOH (1.5 mL), filtered andpurified by preparative chromatography. The stereoisomers were separatedusing chiral SFC HPLC on a Phenomenex Lux C4; 4.6*250 mm; 5 μm column,and a mobile phase consisting of 20% MeOH (containing 0.1% diethylamine)and 80% CO₂ and a flow rate of 50 mL/min to give:

Isomer 1(2S,4R)-6-(3-chlorophenyl)-5′-methyl-2-[(3R)-tetrahydro-2H-pyran-3-yl]-2,3-dihydrospiro[chromene-4,2′-imidazol]-4′-amine:

(23 mg, 12% yield) with retention time 6.77 min: ¹H NMR (500 MHz, CDCl₃)δ ppm 1.70 (m, 4H), 1.86 (m, 1H), 2.02 (ddt, 1H), 2.45 (s, 3H), 2.57 (t,1H), 3.40 (m, 2H), 3.94 (d, 1H), 4.30 (dd, 1H), 4.39 (ddd, 1H), 6.59 (d,1H), 6.98 (d, 1H), 7.24 (m, 1H), 7.29 (m, 2H), 7.34 (dd, 1H), 7.39 (s,1H); MS (ES+) m/z 410 [M+H]⁺.

Isomer 2 with undetermined absolute configuration (19 mg, 10% yield)with retention time 7.85 min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.69 (m,4H), 1.86 (m, 1H), 2.02 (m, 1H), 2.44 (s, 3H), 2.57 (t, 1H), 3.40 (m,2H), 3.94 (d, 1H), 4.30 (dd, 1H), 4.40 (ddd, 1H), 6.59 (d, 1H), 6.98 (d,1H), 7.24 (qd, 1H), 7.28 (m, 2H), 7.33 (dd, 1H), 7.39 (m, 1H); MS (ES+)m/z 410 [M+H]⁺.

Isomer 3 with undetermined absolute configuration (12 mg, 6% yield) withretention time 10.03 min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.68 (m, 4H),1.86 (m, 1H), 2.01 (m, 1H), 2.34 (s, 3H), 2.47 (t, 1H), 3.40 (m, 2H),3.94 (m, 1H), 4.31 (dd, 1H), 4.54 (m, 1H), 6.75 (d, 1H), 6.98 (m, 1H),7.23 (m, 1H), 7.30 (m, 2H), 7.34 (dd, 1H), 7.40 (m, 1H); MS (ES+) m/z410 [M+H]⁺

Isomer 4 (2R,4R)-6-(3-chlorophenyl)-5′-methyl-2-[(3S)-tetrahydro-2H-pyran-3-yl]-1′,2,3,3′-tetrahydrospiro[chromene-4,2′-imidazol]-4′-amine:

(10 mg, 5% yield) with retention time 11.65 min: ¹H NMR (500 MHz, CDCl₃)δ ppm 1.69 (m, 4H), 1.86 (d, 1H), 2.01 (m, 1H), 2.34 (s, 3H), 2.47 (t,1H), 3.40 (m, 2H), 3.95 (d, 1H), 4.31 (dd, 1H), 4.54 (ddd, 1H), 6.76 (d,1H), 6.97 (d, 1H), 7.23 (m, 1H), 7.30 (m, 2H), 7.34 (dd, 1H), 7.40 (m,1H); MS (ES+) m/z 410 [M+H]⁺.

6-Bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine(Isomeric mixture 2 from Example 47 Step 3, 0.146 g, 0.39 mmol) wasreacted with 3-chlorophenylboronic acid (0.091 g, 0.58 mmol) asdescribed above. The isomers were separated using chiral HPLC methods:

Method 1: SFC HPLC with a OD-H; 20*250 mm; 5 μm column and a mobilephase consisting of 15% (IPA/EtOH 50:50 containing 0.1% diethylamine)and 85% CO₂ at a flow rate of 50 mL/min to give:

Isomer 5 with undetermined absolute configuration (29 mg, 15% yield)with retention time 8.94 min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.67 (m,4H), 2.02 (m, 2H), 2.46 (s, 3H), 2.65 (t, 1H), 3.44 (td, 1H), 3.52 (t,1H), 3.95 (m, 2H), 4.46 (m, 1H), 6.60 (d, 1H), 6.99 (d, 1H), 7.24 (m,1H), 7.29 (d, 2H), 7.35 (dd, 1H), 7.39 (s, 1H); MS (ES+) m/z 410 [M+H]⁺.and

Isomer 6 with undetermined absolute configuration (9 mg, 5% yield) withretention time 11.11 min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.60 (m, 4H),1.98 (td, 1H), 2.07 (d, 1H), 2.36 (s, 3H), 2.56 (t, 1H), 3.43 (m, 1H),3.51 (t, 1H), 3.96 (m, 2H), 4.60 (dd, 1H), 6.76 (d, 1H), 6.98 (d, 1H),7.24 (m, 1H), 7.30 (m, 2H), 7.36 (dd, 1H), 7.41 (s, 1H); MS (ES+) m/z410 [M+H]⁺. and

Isomeric mixture 1 was further separated using Method 2: SFC HPLC with aPhenomenex Lux C4; 20*250 mm; 5 μm column, and a mobile phase consistingof 20% MeOH (containing 0.1% diethylamine) and 80% CO₂ at a flow rate of50 mL/min to give:

Isomer 7(2R,4R)-6-(3-chlorophenyl)-5′-methyl-2-[(3R)-tetrahydro-2H-pyran-3-yl]-1′,2,3,3′-tetrahydrospiro[chromene-4,2′-imidazol]-4′-amine:

(8 mg, 4% yield) with retention time 6.64 min: ¹H NMR (500 MHz, CDCl₃) δppm 1.65 (m, 4H), 1.98 (dd, 1H), 2.08 (d, 1H), 2.32 (s, 3H), 2.55 (t,1H), 3.43 (td, 1H), 3.51 (t, 1H), 3.96 (m, 2H), 4.61 (m, 1H), 6.76 (d,1H), 6.97 (d, 1H), 7.23 (m, 1H), 7.30 (m, 2H), 7.34 (dd, 1H), 7.41 (s,1H); MS (ES+) m/z 410 [M+H]⁺. and

Isomer 8 (2 S,4R)-6-(3-chlorophenyl)-5′-methyl-2-[(3S)-tetrahydro-2H-pyran-3-yl]-1′,2,3,3′-tetrahydrospiro[chromene-4,2′-imidazol]-4′-amine:

(25 mg, 13% yield) with retention time 10.30 min: ¹H NMR (500 MHz,CDCl₃) δ ppm 1.68 (m, 4H), 2.01 (m, 2H), 2.43 (s, 3H), 2.64 (t, 1H),3.45 (td, 1H), 3.52 (t, 1H), 3.95 (m, 2H), 4.47 (m, 1H), 6.60 (d, 1H),6.98 (d, 1H), 7.24 (m, 1H), 7.28 (d, 2H), 7.33 (dd, 1H), 7.39 (s, 1H);MS (ES+) m/z 410 [M+H]⁺.

Example 496-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methyl-spiro[chromane-4,2′-imidazole]-4′-amineStep 1:N-(6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-ylidene)-2-methylpropane-2-sulfinamide

Titanium (IV) ethoxide (6.18 mL, 29.48 mmol) was added to a solution of6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-one(Intermediate 28, 4 g, 11.79 mmol) in dry THF (150 mL) under argon. Thesolution was stirred 5 min before addition of2-methylpropane-2-sulfinamide (1.715 g, 14.15 mmol) was made in oneportion. The reaction was refluxed over the weekend (˜70 h) with aheating bath temperature of 80° C. The reaction was cooled to r.t., anddiluted with EtOAc (300 mL). Saturated NaHCO₃ (150 mL) was added undervigorous stirring. After 5 min diatomaceous earth was added and themixture was stirred for another 10 min. The slurry was filtered throughdiatomaceous earth (washed with EtOAc) and the filtrate was evaporatedat reduced pressure. Purification by flash chromatography(EtOAc/heptane) on silica gel gave the title compound (4.93 g, 95%yield): MS (ES+) m/z 442 [M+H]⁺.

Step 2:6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione

A solution of 2-oxopropanethioamide (Intermediate 2, 3.29 g, 31.94 mmol)in dry DMF (15 mL) was added toN-(6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-ylidene)-2-methylpropane-2-sulfinamide(Example 49 Step 1, 4.71 g, 10.65 mmol) in a dried microwave vial underargon. The vial was sealed and heated at 120° C. for 30 min. The productwas not isolated but used directly in the solution in the next reaction:MS (ES−) m/z 421 [M−H]⁻.

Step 3:6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione(Example 49 Step 2), directly from the previous step was dissolved indry DMF (4 mL) in a microwave vial. Ammonia, 7M in MeOH (18 mL, 126mmol) was added. The vial was sealed and the reaction was heated at 100°C. for 60 min in a microwave reactor (fixed hold time). The mixture wasconcentrated and the residue was dissolved in ammonia (7M in MeOH, 18mL, 126 mmol) and heated at 120° C. for 30 min in a microwave reactor.This cycle was repeated three more times. After evaporation of thesolvent, the remaining product was subjected to flash chromatography(0-7% of MeOH(NH₃) in DCM) to give the title compound as a mixture ofisomers (1.29 g, 30% yield over two steps): MS (ES+) m/z 406 [M+H]⁺.

Step 4: Separation of the isomers of6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine(Example 49 Step 3, 1.28 g, 3.15 mmol) was purified using a Gilson RPHPLC system with a X-Bridge C18, 50×250 mm column with gradient elutionof acetonitrile in 0.05 M aq. ammonium acetate. The purification yieldedtwo mixtures of isomers:

Isomeric mixture 1: (182 mg, 14% yield) with retention time 8.11 min: MS(ES+) m/z 406 [M+H]⁺.

Isomeric mixture 2: (608 mg, 47% yield) with retention time 8.68 min: MS(ES+) m/z 406 [M+H]⁺.

Example 506-(3-Chlorophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine

6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine(Isomeric mixture 1 from Example 49 Step 4, 0.08 g, 0.20 mmol),3-chlorophenylboronic acid (0.046 g, 0.30 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g,0.02 mmol), 2 M aq. K₂CO₃ solution (0.197 mL, 0.39 mmol) and 1,4-dioxane(1.5 mL) were mixed in a vial and heated in a microwave reactor at 130°C. for 20 min. When cooled to r.t. the mixture was diluted with DCM,washed with water and dried over Na₂SO₄. The filtrate was concentratedand the product purified by preparative chromatography to yield Isomericmixture 1 of the title compound (30 mg, 35% yield): ¹H NMR (500 MHz,CDCl₃) δ ppm 1.28 (m, 7H), 1.48 (m, 3H), 1.64 (d, 1H), 1.91 (t, 1H),2.11 (m, 1H), 2.40 (s, 3H), 2.51 (t, 1H), 3.74 (td, 1H), 3.85 (td, 1H),4.48 (dd, 1H), 6.81 (d, 1H), 7.01 (d, 1H), 7.26 (m, 1H), 7.32 (d, 2H),7.40 (m, 2H); MS (ES+) m/z 438 [M+H]⁺.

Using the same procedure as above but starting from6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine(Isomeric mixture 2 from Example 49 Step 4, 0.102 g, 0.25 mmol) gaveIsomeric mixture 2 of the title compound (35 mg, 32% yield): ¹H NMR (500MHz, CDCl₃) δ ppm 1.29 (m, 6H), 1.50 (m, 3H), 1.66 (d, 1H), 1.90 (d,1H), 2.17 (m, 1H), 2.51 (s, 3H), 2.62 (m, 1H), 3.74 (td, 1H), 3.86 (dd,1H), 4.29 (dd, 1H), 6.64 (d, 1H), 7.03 (d, 1H), 7.27 (m, 1H), 7.32 (m,2H), 7.40 (m, 2H), 8.18 (s, 1H); MS (ES+) m/z 438 [M+H]⁺.

Example 517′-Bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine

Step 1:N-(7-Bromo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-methylpropane-2-sulfinamide

7-Bromo-3,4-dihydronaphthalen-1(2H)-one (5 g, 22.21 mmol),2-methylpropane-2-sulfinamide (4.04 g, 33.32 mmol) and titanium ethoxide(9.15 mL, 44.43 mmol) were dissolved in 2-Me THF (50 mL) and heated toreflux for 22 h. The reaction was left to cool down to r.t. EtOAc (20mL), NaHCO₃ (sat, 5 mL) and water was added under stirring. The mixturewas left to stand without stirring for 1 h. The organic phase wascollected by filtration, dried over MgSO₄ and concentrated in vacuo togive the title compound (7.29 g) that was used without purification inthe next step: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.34 (s, 9H), 2.00-2.10 (m,2H), 2.77-2.86 (m, 2H), 3.01-3.12 (m, 1H), 3.28 (ddd, 1H), 7.09 (d, 1H),7.50 (dd, 1H), 8.25 (d, 1H), MS (ES+) m/z 328[M+H]⁺.

Step 2: 7-Bromo-3,4-dihydronaphthalen-1(2H)-imine

HCl (4M in 1,4-dioxane) (6.75 mL, 222.07 mmol) was added to a suspensionofN-(7-bromo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-methylpropane-2-sulfinamide(Example 51 Step 1, 7.29 g, 22.2 mmol) in anhydrous 1,4-dioxane (50 mL).The resulting mixture was stirred under a nitrogen atmosphere at r.t.for 1 h. The formed precipitate was filtered off and washed with Et₂O.The solid was then dissolved in DCM and sat. aq. NaHCO₃. The mixture waspoured into a phase separator, the organic layer was collected andconcentrated. The product was used directly in the next step.

Step 3:7′-Bromo-4-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalene]-5(1H)-thione

7-Bromo-3,4-dihydronaphthalen-1(2H)-imine (Example 51 Step 2, 3 g, 13.39mmol) was dissolved in MeOH (70 mL) and THF (10 mL).2-Oxopropanethioamide (4.14 g, 40.16 mmol, Intermediate 2) was added.The solution was heated at 60° C. overnight. The reaction was allowed tocool to r.t. The formed precipitate was filtered off, washed with coldMeOH and dried in vacuo. The mother liquor was concentrated. Thecombined precipitate and concentrated mother liquor was purified usingtwo subsequent flash chromatography (1: 40 g SiO₂, 0-30% 0.2 NH₃ in MeOHin DCM, 2: 80 g SiO₂, 0-10% 0.2 M NH₃ in MeOH in DCM) to yield the titlecompound (1.05 g, 25% yield). MS (ES+) m/z 309 [M+H]⁺.

Step 4:7′-Bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine

7′-Bromo-4-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalene]-5(1H)-thione(Example 51 Step 3, 1 g, 3.23 mmol) was taken up in ammonia (7M in MeOH,15 mL, 105 mmol) and the resulting mixture was heated in the microwavereactor at 110° C. for 30 min. The solvent was evaporated. Ammonia (7Min MeOH, 15 mL, 105 mmol) was added and the reaction was heated againusing MW for 30 min at 110° C. The solvent was evaporated. Ammonia (7Min MeOH, 15 mL, 105 mmol) was added and the reaction was heated againusing MW for 30 min at 110° C. The solvent was evaporated and theresidue was dissolved in EtOAc (20 mL). The resulting mixture wasextracted with 0.1 M citric acid (2×10 mL). The organic layer wasdiscarded while the aqueous phase was basified to pH 12 by addition of50% NaOH (aq) and extracted with DCM (3×20 mL). The organic phase wasdried with a phase separator and concentrated in vacuo to give the titlecompound (0.619 g, 65% yield). 20 mg of the product was purified usingflash chromatography (4 g SiO₂, DCM in 0.1M NH₃ in MeOH) to give thetitle compound (10 mg). ¹H NMR (500 MHz, CDCl₃) δ ppm 1.88-1.99 (m, 2H),2.07-2.16 (m, 1H), 2.20 (dqd, 1H), 2.31-2.37 (m, 3H), 2.92 (t, 2H), 6.68(d, 1H), 7.04 (d, 1H), 7.25 (dd, 1H); ¹H NMR (500 MHz, CD₃OD) δ ppm 1.84(ddd, 1H), 1.94 (ddd, 1H), 2.03-2.12 (m, 1H), 2.15 (dtd, 1H), 2.34 (s,3H), 2.91 (t, 2H), 6.69 (d, 1H), 7.11 (d, 1H), 7.29 (dd, 1H), MS (ES+)m/z 292 [M+H]⁺.

Example 527′-(5-Chloropyridin-3-yl)-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine

Sodium tetrachloropalladate(II) (3.52 mg, 0.01 mmol),3-(di-tert-butylphosphonium)propane sulfonate (6.43 mg, 0.02 mmol),5-chloropyridin-3-ylboronic acid (51.6 mg, 0.31 mmol) and7′-bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine(Example 51 Step 4, 70 mg, 0.24 mmol) were added to a vial.2-Methyl-tetrahydrofuran (1 mL) and K₂CO₃ (2M aq.) (0.359 mL, 0.72 mmol)were added and the mixture was degassed by bubbling N₂ (g). The vial wassealed and heated in a microwave reactor at 90° C. for 30 min. EtOAc (5mL) and water (5 mL) were added and the phases were separated. Theaqueous phase was extracted with EtOAc twice and the combined organiclayers were dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography (4 g SiO₂, 0-10% McOHcontaining 0.1M NH₃ in DCM). The fractions containing product werecombined and concentrated, yielding the title compound (26 mg, 33%yield). ¹H NMR (500 MHz, CD₃OD) δ ppm 1.85-1.94 (m, 1H), 2.01 (ddd, 1H),2.08-2.17 (m, 1H), 2.17-2.27 (m, 1H), 2.35 (s, 3H), 3.02 (t, 2H), 6.84(d, 1H), 7.34 (d, 1H), 7.48 (dd, 1H), 7.97 (t, 1H), 8.48 (d, 1H), 8.57(d, 1H); MS (ES+) m/z 325 [M+H]⁺.

Example 535-Methyl-7′-(5-(prop-1-ynyl)pyridin-3-yl)-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine

The title compound (19 mg, 22% yield), was prepared as described forExample 52 starting from 5-(prop-1-ynyl)pyridin-3-ylboronic acid(Intermediate 15, 66 mg, 0.33 mmol) and7′-bromo-5-methyl-3′,4′-dihydro-2′H-spiro[imidazole-2,1′-naphthalen]-4-amine(Example 51, 75 mg, 0.26 mmol). ¹H NMR (500 MHz, CD₃OD) δ ppm 1.86-1.93(m, 1H), 2.01 (ddd, 1H), 2.08 (s, 3H), 2.09-2.17 (m, 1H), 2.17-2.26 (m,1H), 2.34 (s, 3H), 3.02 (t, 2H), 6.80 (d, 1H), 7.33 (d, 1H), 7.45 (dd,1H), 7.85 (t, 1H), 8.44 (d, 1H), 8.52 (d, 1H); MS (ES+) m/z 329 [M+H]⁺.

Example 546′-Bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-(5′-Bromospiro[cyclobutane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

6′-Bromospiro[cyclobutane-1,2′-inden]-1′(3′H)-one (Intermediate 38, 1.1g, 4.38 mmol), 2-methylpropane-2-sulfinamide (0.96 g, 7.88 mmol), andtitanium ethoxide (1.805 mL, 8.76 mmol) were dissolved in methyl THF (20mL), and heated to reflux overnight. The reaction was allowed to cool tor.t., then it was diluted with EtOAc (150 mL). Water (22 mL) was addeddropwise over 10 min under vigorous stirring and then the mixture wasleft standing without stirring for 1.5 h. The solids were filtered offand the organics were evaporated to give a crude product which waspurified by flash chromatography (eluent: heptane/ethylacetate 8:1) toafford the title compound (2.1 g, 77% yield), used as such in the nextstep: MS (ES+) m/z 354 [M+H]⁺.

Step 2: 6′-Bromospiro[cyclobutane-1,2′-inden]-1′(3′H)-imine

Hydrochloric acid (4M in 1,4-dioxane, 14.89 mL, 59.55 mmol) was added toa solution ofN-(5′-bromospiro[cyclobutane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 54 Step 1, 2.11 g, 5.96 mmol) in anhydrous 1,4-dioxane (60 mL),and the resulting mixture was stirred under an argon atmosphere for 3 h.Et₂O (4 mL) was added and the precipitate was filtered off and washedwith Et₂O, then partitioned between DCM (100 mL), and sat. aq. NaHCO₃(100 mL). The phases were separated and the organic layer concentratedto afford the title compound that was used as such without furtherpurification.

Step 3:6′-Bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

6′-Bromospiro[cyclobutane-1,2′-inden]-1′(3′H)-imine (Example 54 Step 2,1.49 g, 5.96 mmol) and 2-oxopropanethioamide (Intermediate 2, 1.844 g,17.88 mmol) were dissolved in dry MeOH (12 mL), and the resultingsolution was heated at 60° C. under an argon atmosphere overnight. Thereaction was allowed to cool to r.t and was then concentrated to give acrude product which was purified by flash chromatography (eluent:heptane/EtOAc12:1 to 10:1) to afford the title compound (1.62 g, 81%yield): NMR: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.73-2.07 (m, 6H), 2.42 (s,3H), 3.13-3.38 (m, 2H), 7.10 (s, 1H), 7.21 (d, 1H), 7.42-7.47 (m, 1H),9.15 (br. s., 1H); MS (ES+) m/z 337 [M+H]⁺.

Step 4:6′-Bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-r,2″-imidazol]-4″-amine

6′-Bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 54 Step 3, 1.62 g, 4.83 mmol) and ammonia (7M in MeOH, 15.2 mL,106 mmol) were mixed together in a microwave vial. The vial was sealedand the reaction was heated at 90° C. for m 30 min in a microwavereactor. The mixture was concentrated and the residue was dissolved inammonia (7M in MeOH, 15.2 mL, 106 mmol), and heated once more at 90° C.for 30 min in a microwave reactor. This cycle was repeated four moretimes. After evaporation of the solvent, the crude was acidified with 2M aq. hydrochloric acid, and washed with EtOAc. The aqueous phase wastreated with 2M NaOH until basic pH was reached and then it wasextracted with EtOAc. The organic phase was dried over MgSO₄ andconcentrated. The organic phase was then acidified with 2M citric acid.The aqueous phase was treated with 2M NaOH until basic pH was reachedand then it was extracted with EtOAc. The organic phases containing thetitle compound were combined, dried over MgSO₄ and concentrated. Theresidue was dissolved in EtOAc and was washed with 50% aq. NaOH Theorganic layer was dried over MgSO₄ and concentrated to afford the titlecompound (1.0 g, 65% yield): NMR: ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.48-1.67 (m, 4H), 1.73-1.86 (m, 1H), 2.08-2.17 (m, 1H), 2.19 (s, 3H),3.06-3.20 (m, 2H), 6.65 (br. s., 2H), 6.71 (d, 1H), 7.26 (d, 1H), 7.35(dd, 1H); MS (ES+) m/z 318 [M+H]⁺.

Example 556′-(5-Chloropyridin-3-yl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine

Sodium tetrachloropalladate (II) (2.77 mg, 9.43 μmol),3-(di-tert-butylphosphonium)propane sulfonate (5.06 mg, 0.02 mmol),5-chloropyridin-3-ylboronic acid (40.6 mg, 0.25 mmol) and6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 54, 60 mg, 0.19 mmol), was added to a vial.2-Methyl-tetrahydrofuran (1 mL) and 2 M aq. K₂CO₃ (0.283 mL, 0.57 mmol)was added and the mixture was degassed by bubbling N₂ (g). The vial wassealed and heated in a microwave reactor at 90° C. for 30 min. EtOAc (5mL) and water (5 mL) were added and the phases were separated. The aqphase was extracted with EtOAc and the combined organic layers weredried over MgSO₄, filtered and concentrated in vacuo. Purification byflash chromatography using a gradient of 0-10% MeOH, containing 1.2% 7MNH₃ in MeOH, in DCM, afforded 51 mg of the title compound (77% yield).¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.62 (m, 4H) 1.83 (d, 1H) 2.16 (s, 1H)2.21 (s, 3H) 3.23 (d, 2H) 6.60 (s, 2H) 6.94 (d, 1H) 7.43 (d, 1H) 7.58(dd, 1H) 8.10 (t, 1H) 8.57 (d, 1H) 8.71 (d, 1H); MS (ES+) m/z 351[M+H]⁺.

Example 565″-Methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (60 mg, 68% yield) was prepared by the methoddescribed in Example 55, starting from6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 54) (80 mg, 0.25 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronicacid (Intermediate 15, 53 mg, 0.33 mmol). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.59 (m, 4H) 1.83 (d, 1H) 2.09 (s, 3H) 2.16 (d, 1H) 2.21 (s, 3H)3.23 (m, 2H) 6.60 (s, 2H) 6.89 (d, 1H) 7.41 (d, 1H) 7.54 (dd, 1H) 7.91(t, 1H) 8.52 (d, 1H) 8.67 (d, 1H). MS (ES+) m/z 355 [M+H]⁺.

Example 57 Separation of the isomers of5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine

The isomers of5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 56, 47 mg, 0.13 mmol) were separated using a SFC BergerMultigram II preparative HPLC, with a Chiralcel OD-H; 20*250 mm; 5 μmcolumn, and a mobile phase consisting of 30% MeOH (containing 0.1% DEA)and 70% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (16 mg, 34% yield)with retention time 2.4 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.58 (m,4H), 1.83 (m, 1H), 2.09 (s, 3H), 2.16 (m, 1H), 2.21 (s, 3H), 3.23 (m,2H), 6.59 (m, 2H), 6.89 (m, 1H), 7.41 (m, 1H), 7.55 (m, 1H), 7.91 (m,1H), 8.52 (m, 1H), 8.67 (m, 1H); MS (APCI+) m/z 355 [M+H]⁺; andIsomer 2 with undetermined absolute configuration (15 mg, 33% yield)with retention time 7.2 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.61 (br.s., 4H), 1.82 (m, 1H), 2.09 (s, 3H), 2.16 (m, 1H), 2.21 (s, 3H), 3.23(d, 2H), 6.60 (s, 2H), 6.89 (d, 1H), 7.41 (d, 1H), 7.54 (d, 1H), 7.91(t, 1H), 8.52 (d, 1H), 8.67 (d, 1H); MS (APCI+) m/z 355 [M+H]⁺.

Example 58 6′-(Cyclopropylethynyl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine

To a solution of6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 54, 0.10 g, 0.31 mmol) in DMF (10 mL) under argon was addedethynylcyclopropane (0.031 g, 0.47 mmol),tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) andtriethylamine (1.31 mL, 9.43 mmol). The reaction mixture was stirred atr.t. for 5 min before addition of cuprous iodide (8.98 mg, 0.05 mmol).The reaction mixture was stirred overnight at 65° C. The reactionmixture was partitioned between sat aq. NaHCO₃ and EtOAc. The organicphase was dried over MgSO₄ and concentrated to give a crude productwhich was purified by preparative chromatography to afford the titlecompound (0.046 g, 48% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.60-0.73(m, 2H), 0.77-0.89 (m, 2H), 1.46 (tt, 1H), 1.50-1.65 (m, 4H), 1.72-1.85(m, 1H), 2.08-2.16 (m, 1H), 2.18 (s, 3H), 3.07-3.23 (m, 2H), 6.54 (d,1H), 6.60 (s, 2H), 7.16 (dd, 1H), 7.20-7.27 (m, 1H); MS (ES+) m/z 304[M+H]⁺.

Example 59 6′-(3,3-Dimethylbut-1-yn-1-yl)-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine

To a solution of6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 54, 0.100 g, 0.31 mmol) in DMF (10 mL) under argon was added 3,3-dimethylbut-1-yne (0.039 g, 0.47 mmol),tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) andtriethylamine (1.31 mL, 9.43 mmol). The reaction mixture was stirred atr.t. for 5 min before addition of cuprous iodide (8.98 mg, 0.05 mmol).The reaction mixture was stirred overnight at 65° C. and thenpartitioned between sat aq. NaHCO₃ and EtOAc. The organic phase wasdried over MgSO₄ and concentrated to give a crude product which waspurified by preparative chromatography to afford the title compound(0.039 g, 38% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.24 (s, 9H),1.47-1.66 (m, 4H), 1.73-1.84 (m, 1H), 2.09-2.17 (m, 1H), 2.18 (s, 3H),3.16 (d, 2H), 6.53 (d, 1H), 6.60 (s, 2H), 7.14 (dd, 1H), 7.24 (d, 1H);MS (ES+) m/z 320 [M+H]⁺.

Example 60(1r,4r)-6′-(5-Chloro-6-methylpyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (287 mg,1.13 mmol),(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19, 213 mg, 0.57 mmol) and potassium acetate (167 mg, 1.70mmol) and dioxane (3 mL) were added and the mixture was degassed with astream of argon (g) for a couple of min. PdCl₂(dppf) CH₂Cl₂ (32.4 mg,0.04 mmol) was added and the mixture was heated to reflux for 1.5 hunder N₂ atmosphere.4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (120 mg,0.47 mmol) was added and the reaction was heated to reflux overnight.The volatiles were removed in vacuo and 80 mg of the residue((1r,4r)-4-methoxy-5″-methyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(MS (ES+) m/z 424 [M+H]⁺) was mixed with5-bromo-3-chloro-2-methylpyridine (Intermediate 43, 47 mg, 0.23 mmol),K₂CO₃ (0.38 mL, 0.76 mmol) and dioxane (2 mL). The mixture was degassedwith a stream of argon (g) for a couple of min. PdCl₂(dppf) CH₂Cl₂adduct (138 mg, 0.19 mmol) was added. The vial was sealed and heated ina microwave reactor at 140° C. for 30 min. EtOAc was added and themixture was washed with brine and water. The organic phase was driedwith MgSO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (12 g SiO₂, 0-20% MeOH containing 0.1 MNH₃ in DCM). The crude product was purified with preparativechromatography. The fractions containing product were combined andconcentrated. The water phase was extracted with DCM and the phases wereseparated using a phase separator. The organic phase was concentrated invacuo yielding the title compound (5 mg, 6% yield): ¹H NMR (CD₃OD) δ ppm1.11 (td, 1H), 1.24-1.43 (m, 2H), 1.49 (td, 1H), 1.63 (td, 2H),1.90-2.00 (m, 2H), 2.32 (s, 3H), 2.61 (s, 3H), 3.04-3.12 (m, 1H), 3.15(d, 1H), 3.25 (d, 1H), 3.33 (s, 3H), 6.99 (d, 1H), 7.47 (d, 1H), 7.55(dd, 1H), 7.99 (d, 1H), 8.51 (d, 1H); MS (MM-ES+APCI)+ m/z 423 [M+H]⁺.

Example 61(1r,1′R,4R)-6′-(5-Chloro-6-methylpyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,1′R,4R)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 0.4 g,0.66 mmol) was dissolved in 2-methyl-tetrahydrofuran (5 mL). KOH (0.4 g,7.13 mmol) in water (3 mL) was added. The reaction mixture was stirredfor 30 min before the water phase was removed and the residue was washedwith 2M K₂CO₃ solution (3 mL). The aqueous phase was removed and theorganic phase was transferred to a microwave vial.3-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Intermediate 44, 0.200 g, 0.79 mmol) was added followed by K₂CO₃ (2.0M, 0.986 mL, 1.97 mmol). Ar (g) was bubbled through the mixture. Sodiumtetrachloropalladate(II) (9.67 mg, 0.03 mmol) and3-(di-tert-butylphosphonium)propane sulfonate (0.018 g, 0.07 mmol) wereadded and the vial was closed and heated with MW for 30 min at 100° C.After cooling to r.t., water and 2-Me THF were added and the water phasewas eliminated. The organic phase was washed with brine and water andconcentrated in vacuo. The product was purified using flashchromatography (40 g SiO₂, gradient elution 0-100% EtOAc in heptane)followed by flash chromatography (40 g SiO₂, gradient elution 0-10% MeOH(containing 0.2 M NH₃) in DCM) to give the title compound (0.065 g, 23%yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.90-1.02 (m, 1H), 1.09-1.31 (m,2H), 1.35-1.55 (m, 3H), 1.83 (d, 2H), 2.17 (s, 3H), 2.52-2.59 (m, 3H),2.89-3.03 (m, 2H), 3.03-3.13 (m, 1H), 3.19 (s, 3H), 6.54 (br. s., 2H),6.84 (s, 1H), 7.40 (d, 1H), 7.54 (d, 1H), 8.00 (s, 1H), 8.58 (s, 1H); MS(ES+) m/z 423 [M+H]⁺.

Example 62(1r,4r)-6′-(5-Chloro-2-methylpyridin-3-yl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

3-Bromo-5-chloro-2-methylpyridine (Intermediate 41, 47 mg, 0.23 mmol),(1r,4r)-4-methoxy-5″-methyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(prepared in Example 60, 80 mg, 0.19 mmol), K₂CO₃ (2 M aq. solution,0.38 mL, 0.76 mmol) and dioxane (2 mL) were added and the mixture wasdegassed with a stream of argon for a couple of min. PdCl₂(dppf) CH₂Cl₂adduct (138 mg, 0.19 mmol) was added. The vial was sealed and heated ina microwave reactor at 140° C. for 30 min. EtOAc was added and thereaction was washed with brine and water. The organic phase was driedwith MgSO₄, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (12 g SiO₂, 0-20% MeOH containing 0.1 MNH₃ in DCM). The crude product was purified with preparativechromatography. The fractions containing product were combined,concentrated and freeze dried yielding the title compound (5 mg, 6%yield): ¹H NMR (CD₃OD) δ ppm 1.07-1.19 (m, 1H), 1.29-1.44 (m, 2H), 1.49(td, 1H), 1.57-1.72 (m, 2H), 1.92-2.00 (m, 2H), 2.30 (s, 3H), 2.37 (s,3H), 3.04-3.13 (m, 1H), 3.17 (d, 1H), 3.26 (d, 1H), 3.34 (s, 3H),6.66-6.72 (m, 1H), 7.26 (dd, 1H), 7.46 (d, 1H), 7.60 (d, 1H), 8.38 (d,1H); MS (MM-ES+APCI)+ m/z 423 [M+H]⁺.

Example 63(1r,4r)-4-Methoxy-5″-methyl-6′-[4-methyl-5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

A suspension of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (160 mg,0.63 mmol), 3-bromo-4-methyl-5-(prop-1-ynyl)pyridine (Intermediate 45,66 mg, 0.31 mmol) and potassium acetate (93 mg, 0.94 mmol) in dioxane (3mL) was degassed with a stream of argon for a couple of min. PdCl₂(dppf)CH₂Cl₂ (13 mg, 0.02 mmol) was added and the mixture was heated at refluxunder N₂ for 4 h. The mixture was allowed to cool, filtered andconcentrated in vacuo. The obtained residue (80 mg,4-methyl-3-(prop-1-ynyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)was mixed with sodium tetrachloropalladate(II) (4 mg, 0.01 mmol),3-(di-tert-butylphosphonium)propane sulfonate (6 mg, 0.02 mmol), and(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19, 90 mg, 0.24 mmol) in dioxane (3 mL). The mixture wasdegassed with a stream of argon for a couple of min. and then heated atreflux. The reaction mixture was allowed to cool and the solvent wasremoved in vacuo. The residue was partitioned between water and EtOAc.The organic phase was dried (Na₂SO₄) and evaporated to give a crudeproduct which was purified by flash chromatography (4 g SiO₂,heptane-(EtOAc/MeOH/NH₃ 90:10:1) gradient. The obtained material waspurified by preparative chromatography. Fractions containing the productwere pooled and the organic solvent was removed in vacuo. The residuewas partitioned between 1 M NaOH and EtOAc. The organic phase was dried(Na₂SO₄) and evaporated to give an oily residue which was solidified byco-evaporation with acetonitrile to give the title compound (15 mg, 15%yield) after drying in vacuo at 40° C.: ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.98 (t, 1H), 1.11-1.34 (m, 2H), 1.34-1.57 (m, 3H), 1.83 (d, 2H), 2.13(m, 9H), 2.87-3.13 (m, 3H), 3.20 (s, 3H), 6.50 (d, 3H), 7.18 (d, 1H),7.39 (d, 1H), 8.16 (br. s., 1H), 8.46 (br. s., 1H); MS (APCI⁺) m/z 427[M+H]⁺.

Example 64 (1r,4r)-6′-Bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine Step 1:(1r,4r)-6′-Bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

HCl (4M in 1,4-dioxane, 1.807 mL, 7.23 mmol) was added to a solution ofN-((1r,4r))-5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 19 Method B Step 1, 0.60 g, 1.45 mmol) in anhydrous 1,4-dioxane(3 mL) and the resulting mixture was stirred under a nitrogen atmosphereat r.t. for 90 min. A precipitate had formed. Et₂O (15 mL) was added andthe solid was filtered off and washed with Et₂O (10 mL). The solid waspartitioned between DCM (20 mL) and sat. aq. NaHCO₃ (20 mL). The phaseswere separated and the organic layer was dried over Na₂SO₄ andconcentrated to give crude(1r,4r)-6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(1.658 g) that was mixed with 2-oxobutanethioamide (Intermediate 29,1.891 g, 16.14 mmol) in MeOH (50 mL). The resulting mixture was refluxedfor 18 h. The reaction mixture was concentrated and the product waspurified by flash chromatography on silica gel, (gradient elution 0 to50% EtOAc in n-heptane) to give the title compound (1.8 g, 82% yield):¹H NMR (500 MHz, CDCl₃) δ ppm 1.17 (td, 1H), 1.33 (m, 6H), 1.63 (m, 1H),1.75 (m, 1H), 2.02 (m, 2H), 2.80 (m, 2H), 3.09 (m, 3H), 3.35 (s, 3H),7.04 (d, 1H), 7.21 (d, 1H), 7.45 (dd, 1H), 8.97 (br. s., 1H); MS (ES+)m/z 407 [M+H]⁺.

Step 2:(1r,4r)-6′-Bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 64 step 1, 0.32 g, 0.80 mmol) was dissolved in ammonia (7Msolution in MeOH, 7.04 mL, 49.31 mmol) and the mixture was heated in amicrowave oven at 90° C. for 2 h. The mixture was concentrated,re-dissolved in ammonia (7M solution in MeOH, 7.04 mL, 49.31 mmol) andheated at 90° C. for 30 min. This procedure was repeated one more time.The solvent was concentrated in vacuo and the residue was partitionedbetween citric acid (2 M aq. solution, 10 mL) and EtOAc (5 mL). Theaqueous layer was neutralized with solid NaHCO₃ until gas evolutionceased and the product was extracted with EtOAc (50 mL). The organiclayer washed with brine, dried over Na₂SO₄ and concentrated at reducedpressure to give the title compound (0.168 g, 54% yield): ¹H NMR (500MHz, CDCl₃) δ ppm 1.08 (td, 1H), 1.38 (m, 6H), 1.67 (m, 2H), 1.96 (m,2H), 2.62 (m, 2H), 3.06 (m, 1H), 3.12 (m, 2H), 3.34 (s, 3H), 6.87 (d,1H), 7.20 (d, 1H), 7.36 (dd, 1H); MS (ES+) m/z 390 [M+H]⁺.

Example 65(1r,4r)-6′-(5-Chloropyridin-3-yl)-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

A mixture of(1r,4r)-6′-bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 64, 0.084 g, 0.22 mmol), 5-chloropyridin-3-ylboronic acid(0.034 g, 0.22 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.016 g,0.02 mmol), K₂CO₃ (2 M aq. solution, 0.215 mL, 0.43 mmol) and1,4-dioxane (2 mL) were mixed in a vial and heated in a microwavereactor at 130° C. for 20 min. When cooled to r.t. the mixture wasdiluted with DCM, washed with water, dried over Na₂SO₄, andconcentrated. The product was purified by preparative chromatography togive the title compound (46 mg, 51% yield): ¹H NMR (500 MHz, CDCl₃) δppm 1.12 (td, 1H), 1.38 (m, 6H), 1.72 (m, 2H), 2.03 (m, 2H), 2.74 (q,2H), 3.11 (m, 1H), 3.23 (d, 1H), 3.30 (d, 1H), 3.35 (s, 3H), 6.99 (s,1H), 7.50 (m, 2H), 7.79 (t, 1H), 8.35 (s, 1H), 8.52 (d, 1H), 8.63 (m,1H); MS (ES+) m/z 423 [M+H]⁺.

Example 66 Separation of the isomers of(1r,4r)-6′-(5-chloropyridin-3-yl)-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-(5-Chloropyridin-3-yl)-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 65, 39 mg, 0.09 mmol) was subjected to chiral HPLC separationusing a SFC Berger Multigram II system with a Chiralcel OD-H column(4.6*250 mm; 5 μm) and a mobile phase consisting of 25% MeOH (containing0.1% DEA) and 75% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (15 mg, 39% yield)with retention time 3.2 min: ¹H NMR (600 MHz) δ ppm 1.12 (td, 1H), 1.32(t, 3H), 1.42 (m, 3H), 1.71 (t, 2H), 1.97 (d, 2H), 2.63 (m, 2H), 3.08(m, 1H), 3.24 (m, 2H), 3.35 (s, 3H), 6.90 (s, 1H), 7.44 (s, 2H), 7.78(s, 1H), 8.49 (m, 1H), 8.62 (s, 1H); MS (MM-ES+APCI)+ m/z 423 [M+H]⁺.

and

Isomer 2 with undetermined absolute configuration (11 mg, 29% yield)with retention time 8.9 min: ¹H NMR (600 MHz, CDCl₃) δ ppm 1.11 (m, 1H)1.32 (t, 3H) 1.39 (m, 2H) 1.50 (m, 1H) 1.72 (t, 2H) 1.97 (d, 2H) 2.61(dquin, 2H) 3.08 (m, 1H) 3.24 (m, 2H) 3.35 (s, 3H) 6.89 (s, 1H) 7.43 (m,2H) 7.78 (s, 1H) 8.49 (m, 1H) 8.62 (s, 1H); MS (MM-ES+APCI)+ m/z 423[M+H]⁺.

Example 67(1r,4r)-5″-Ethyl-4-methoxy-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (40 mg, 43% yield) was prepared by the methoddescribed in Example 65 starting from(1r,4r)-6′-bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 64, 84 mg, 0.22 mmol), and 5-(prop-1-ynyl)pyridin-3-ylboronicacid (Intermediate 15, 35 mg, 0.22 mmol): ¹H NMR (500 MHz, CDCl₃) δ ppm1.12 (td, 1H), 1.34 (t, 3H), 1.41 (m, 3H), 1.70 (dd, 1H), 1.77 (d, 1H),2.05 (m, 2H), 2.09 (s, 3H), 2.80 (q, 2H), 3.11 (m, 1H), 3.22 (d, 1H),3.30 (d, 1H), 3.35 (s, 3H), 7.03 (s, 1H), 7.46 (m, 1H), 7.52 (m, 1H),7.79 (s, 1H), 8.54 (m, 1H), 8.64 (m, 1H); MS (ES+) m/z 427 [M+H]⁺.

Example 68 Separation of the isomers of(1r,4r)-5″-ethyl-4-methoxy-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-5″-Ethyl-4-methoxy-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 67, 29 mg, 0.07 mmol) was subjected to chiral HPLC separationusing a SFC Berger Multigram 11 system with a Chiralcel OD-H column(4.6*250 mm; 5 μm) and a mobile phase consisting of 25% MeOH (containing0.1% DEA) and 75% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (11 mg, 39% yield)with retention time 3.4 min: ¹H NMR (600 MHz, CDCl₃) δ ppm 1.12 (m, 1H),1.32 (t, 3H), 1.41 (m, 3H), 1.72 (m, 2H), 1.99 (br. s., 2H), 2.09 (s,3H), 2.66 (m, 2H), 3.09 (m, 1H), 3.24 (m, 2H), 3.35 (s, 3H), 6.93 (s,1H), 7.44 (q, 2H), 7.77 (s, 1H), 8.53 (br. s., 1H), 8.62 (br. s., 1H);MS (MM-ES+APCI)+ m/z 427 [M+H]⁺.

and

Isomer 2 with undetermined absolute configuration (11 mg, 39% yield)with retention time 8.7 min: ¹H NMR (600 MHz, CDCl₃) δ ppm 1.11 (m, 1H),1.32 (t, 3H), 1.39 (m, 2H), 1.49 (m, 1H), 1.72 (m, 2H), 1.97 (d, 2H),2.09 (s, 3H), 2.61 (m, 2H), 3.08 (m, 1H), 3.23 (m, 2H), 3.35 (s, 3H),6.89 (s, 1H), 7.43 (m, 2H), 7.77 (s, 1H), 8.53 (s, 1H), 8.61 (s, 1H); MS(MM-ES+APCI)+ m/z 427 [M+H]⁺.

Example 695-[(1r,4r)-4″-Amino-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]pyridine-3-carbonitrile

The title compound (44 mg, 52% yield) was prepared by the methoddescribed in Example 65 starting from(1r,4r)-6′-bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 64, 80 mg, 0.20 mmol), and 5-cyanopyridin-3-ylboronic acid(0.030 g, 0.20 mmol): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.14 (td, 1H), 1.37(m, 6H), 1.72 (m, 2H), 2.04 (m, 2H), 2.73 (q, 2H), 3.10 (m, 1H), 3.24(d, 1H), 3.31 (d, 1H), 3.36 (s, 3H), 7.00 (s, 1H), 7.52 (m, 2H), 8.06(t, 1H), 8.83 (d, 1H), 8.95 (d, 1H); MS (ES+) m/z 414 [M+H]⁺.

Example 703-[(1r,4r)-4″-amino-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]benzonitrile

The title compound (73 mg, 85% yield) was prepared by the methoddescribed in Example 65 starting from(1r,4r)-6′-bromo-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 64, 81 mg, 0.21 mmol), and 3-cyanophenylboronic acid (30 mg,0.21 mmol): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.13 (td, 1H), 1.38 (m, 6H),1.72 (m, 2H), 2.05 (m, 2H), 2.76 (q, 2H), 3.11 (m, 1H), 3.22 (d, 1H),3.30 (d, 1H), 3.35 (s, 3H), 7.00 (s, 1H), 7.46 (m, 1H), 7.52 (m, 2H),7.61 (d, 1H), 7.73 (d, 1H), 7.78 (s, 1H), 8.32 (br. s., 1H); MS (ES+)m/z 413 [M+H]⁺.

Example 71 Separation of the isomers of3-[(1r,4r)-4″-amino-5″-ethyl-4-methoxy-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]benzonitrile

3-[(1r,4r)-4″-Amino-5″-ethyl-4-methoxy-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]benzonitrile(Example 70, 34 mg, 0.08 mmol) was subjected to chiral HPLC separationusing a SFC Berger Multigram II system with a Chiralcel OD-H column(4.6*250 mm; 5 μm) and a mobile phase consisting of 25% MeOH (containing0.1% DEA) and 75% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (22 mg, 65% yield)with retention time 3.4 min: ¹H NMR (600 MHz, CDCl₃) δ ppm 1.12 (td,1H), 1.33 (t, 3H), 1.42 (m, 3H), 1.72 (m, 2H), 1.98 (d, 2H), 2.63 (m,2H), 3.08 (m, 1H), 3.24 (m, 2H), 3.35 (s, 3H), 6.90 (s, 1H), 7.43 (m,2H), 7.48 (t, 1H), 7.57 (d, 1H), 7.73 (d, 1H), 7.78 (s, 1H); MS(MM-ES+APCI)+ m/z 413 [M+H]⁺.

and

Isomer 2 with undetermined absolute configuration (19 mg, 56% yield)with retention time 11.6 min: ¹H NMR (600 MHz, CDCl₃) δ ppm 1.11 (m,1H), 1.32 (t, 3H), 1.39 (m, 2H), 1.48 (m, 2H), 1.72 (t, 2H), 1.97 (d,2H), 2.62 (dquin, 2H), 3.08 (m, 1H), 3.23 (m, 2H) 3.35 (s, 3H), 6.89 (s,1H), 7.42 (s, 2H), 7.47 (t, 1H), 7.57 (d, 1H), 7.72 (d, 1H), 7.78 (s,1H); MS (MM-ES+APCI)+ m/z 413 [M+H]⁺.

Example 72(1r,4r)-6′-[5-(But-1-yn-1-yl)pyridin-3-yl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 83 mg, 0.22 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (9.0 mg, 0.01 mmol), 5-(but-1-ynyl)pyridin-3-ylboronic acid (60mg, 0.34 mmol) and Cs₂CO₃ (144 mg, 0.44 mmol) were weighed into amicrowave vial. A mixture of DME, water and EtOH (6:3:1) (5 mL) wasadded and the vial was flushed with argon. The resulting mixture washeated to 120° C. in a microwave reactor for 1 h. The mixture wasdiluted with EtOAc and filtered. The solvents were evaporated and theresidue was purified by preparative chromatography to give 37 mg (39%yield) of the title compound: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.12 (td,1H), 1.27 (t, 2H), 1.29-1.44 (m, 2H), 1.50 (td, 1H), 1.65-1.77 (m, 2H),1.92-2.01 (m, 2H), 2.31 (s, 3H), 2.45 (q, 2H), 3.02-3.15 (m, 1H),3.17-3.28 (m, 2H), 3.34 (s, 3H), 6.90 (s, 1H), 7.41 (s, 2H), 7.78 (t,1H), 8.53 (d, 1H), 8.61 (d, 1H); MS (APCI+) m/z 427 [M+H]⁺.

Example 73(1r,1′R,4R)-4″-Amino-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-ol

(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 20a Isomer 1, 519 mg, 1.26 mmol) was added to(methylthio)trimethylsilane (1.249 mL, 8.81 mmol) in 1,2-dichloroethane(8 mL), followed by zinc iodide (2.0 g, 6.29 mmol) andtetrabutylammonium iodide (697 mg, 1.89 mmol). The suspension wasstirred at 60° C. for 2 days. The reaction mixture was filtered and thefiltrate was washed with a 5% aq solution of barium hydroxide then withwater. After evaporation of the solvent, the residue was subjected toflash chromatography (0-7% MeOH (containing NH₃) in DCM) to give thetitle compound (100 mg, 20% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.89-1.02 (m, 1H) 1.13-1.35 (m, 2H) 1.41 (br. s., 3H) 1.66 (br. s., 2H)2.09 (s, 3H) 2.17 (s, 3H) 3.04 (dd, 2H) 3.18-3.27 (m, 1H) 4.55 (br. s,1H) 6.53 (br. s., 2H) 6.82 (s, 1H) 7.41 (d, 1H) 7.53 (dd, 1H) 7.90 (s,1H) 8.51 (d, 1H) 8.66 (d, 1H); MS (ES+) m/z 399 [M+H]⁺.

Example 743-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methylbenzonitrile

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 414 mg, 1.10 mmol), potassium acetate (216mg, 2.20 mmol), bis(pinacolato)diboron (307 mg, 1.21 mmol) andPdCl₂(dppf)-dichloromethane adduct (44.9 mg, 0.06 mmol) were taken up indioxane (8 mL) in a Biotage 10-20 mL microwave vial. The reaction vesselwas sealed and heated at 130° C. for 35+20 min in a Biotage Initiator.The obtained mixture containing(1r,4r)-4-methoxy-5″-methyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-aminemixture was used directly. K₂CO₃ (2 M aq., 2.20 mL, 4.41 mmol),Pd(Ph₃P)₄ (63.7 mg, 0.06 mmol) and 3-bromo-5-methylbenzonitrile(Intermediate 50, 216 mg, 1.10 mmol) in dioxane (2 mL) were added. Thereaction vessel was sealed and heated at 130° C. for 20 min in a BiotageInitiator. After cooling, the vessel was uncapped, the mixture wasdiluted with DCM, washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The product was purified by preparativechromatography to give the title product compound (62 mg, 16% yield): ¹HNMR (600 MHz, DMSO-d₆) δ ppm 0.97 (td, 1H) 1.11-1.30 (m, 2H) 1.35-1.52(m, 3H) 1.83 (d, 2H) 2.18 (s, 3H) 2.39 (s, 3H) 2.90-2.97 (m, 1H)2.97-3.11 (m, 2H) 3.20 (s, 3H) 6.53 (br. s, 2H) 6.82 (s, 1H) 7.39 (d,1H) 7.52 (d, 1H) 7.59 (s, 1H) 7.67 (s, 1H) 7.77 (s, 1H); MS (ES+) m/z413 [M+H]⁺.

Example 753-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-fluorobenzonitrile

A mixture of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 300 mg, 0.80 mmol),3-cyano-5-fluorophenylboronic acid (145 mg, 0.88 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (59.0 mg,0.07 mmol), K₂CO₃, 2 M aq. solution (0.797 mL, 1.59 mmol) and1,4-dioxane (5 mL) were mixed in a vial and heated in a microwavereactor at 130° C. for 20 min. When cooled to r.t. the mixture wasdiluted with DCM, washed with water and dried over Na₂SO₄. The filtratewas concentrated and the product purified by preparative chromatographyto give the title compound (190 mg, 57% yield): ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.90-1.03 (m, 1H) 1.11-1.31 (m, 2H) 1.36-1.53 (m, 3H)1.82 (d, 2H) 2.18 (s, 3H) 2.88-2.98 (m, 1H) 2.96-3.12 (m, 2H) 3.19 (s,3H) 6.56 (br. s, 2H) 6.90 (d, 1H) 7.40 (d, 1H) 7.58 (dd, 1H) 7.73-7.84(m, 2H) 7.90 (t, 1H); MS (ES+) m/z 417 [M+H]⁺.

Example 76 Separation of the isomers of3-[(1r,4r)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-fluorobenzonitrile

3-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-fluorobenzonitrile(Example 75, 157 mg, 0.378 mmol) was dissolved in MeOH/DEA and theresulting solution was injected (2 separate injections) on a SFC BergerMultigram II system equipped with a LuxC4 (4.6*250 mm; 5 μm) columnusing a mobile phase consisting of 30% MeOH (containing 0.1% DEA) and70% CO₂ at a flowrate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (56 mg, 36% yield)with retention time 4.8 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88-1.05(m, 1H) 1.09-1.30 (m, 2H) 1.35-1.52 (m, 3H) 1.83 (d, 2H) 2.18 (s, 3H)2.88-2.98 (m, 1H) 3.04 (q, 2H) 3.19 (s, 3H) 6.53 (br. s, 2H) 6.90 (s,1H) 7.41 (d, 1H) 7.59 (d, 1H) 7.74-7.84 (m, 2H) 7.90 (s, 1H); MS (ES+)m/z 417 [M+H]⁺; and

Isomer 2 with undetermined absolute configuration (56 mg, 36% yield)with retention time 13 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.92-1.06(m, 1H) 1.11-1.30 (m, 2H) 1.36-1.56 (m, 3H) 1.83 (d, 2H) 2.18 (s, 3H)2.89-2.97 (m, 1H) 3.04 (q, 2H) 3.20 (s, 3H) 6.53 (br. s., 2H) 6.90 (s,1H) 7.41 (d, 1H) 7.59 (d, 1H) 7.73-7.83 (m, 2H) 7.91 (s, 1H); MS (ES+)m/z 417

[M+H]⁺.

Example 776′-Bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-(5′-Bromospiro[cyclopropane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

The title compound was prepared in quantitative yield as described forExample 19 Method A Step 1 starting from6′-bromospiro[cyclopropane-1,2′-inden]-1′(3′H)-one (Intermediate 52,1.41 g, 5.96 mmol): MS (ES+) m/z 342 [M+H]⁺.

Step 2: 6′-Bromospiro[cyclopropane-1,2′-inden]-1′(3′H)-imine

The title compound (0.61 g, 44% yield) was prepared as described forExample 19 Method A Step 2 starting fromN-(5′-bromospiro[cyclopropane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 77 Step 1, 2.0 g, 5.88 mmol): MS (ES+) m/z 236 [M+H]⁺.

Step 3:6′-Bromo-5″-methyl-311-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

The title compound (0.51 g, 63% yield) was prepared as described forExample 19 Method A Step 3 starting from6′-bromospiro[cyclopropane-1,2′-inden]-1′(3′H)-imine (Example 77 Step 2,0.61 g, 2.54 mmol). ¹H NMR (500 MHz, CDCl₃) δ ppm 0.55-0.62 (m, 1H),0.64-0.73 (m, 2H), 0.79-0.87 (m, 1H), 2.39 (s, 3H), 2.91 (d, 1H), 3.36(d, 1H), 7.09 (d, 1H), 7.21 (d, 1H), 7.48 (dd, 1H), MS (ES+) m/z 321[M+H]⁺.

Step 46′-Bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (0.33 g, 68% yield) was prepared as described forExample 19 Method A Step 4 starting from6′-bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 77 step 3, 0.51 g, 1.59 mmol): ¹H NMR (500 MHz, CDCl₃) δ ppm0.23 (ddd, 1H), 0.42-0.57 (m, 1H), 0.65 (dt, 1H), 0.79 (ddd, 1H), 2.29(s, 3H), 2.87 (d, 1H), 3.42 (d, 1H), 6.90 (d, 1H), 7.19 (d, 1H), 7.37(dd, 1H), MS (ES+) m/z 304 [M+H]⁺.

Example 783-(4″-Amino-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-6′-yl)-5-chlorobenzonitrile

6′-Bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 77, 0.10 g, 0.33 mmol),3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

(Intermediate 35, 0.121 g, 0.46 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.048 g,0.07 mmol), 2M aq. K₂CO₃ (0.493 mL, 0.99 mmol) and THF (1 mL) were addedto microwave vial. The mixture was degassed by bubbling N₂ (g) throughit. The vial was sealed and heated in a microwave reactor at 130° C. for30 min. [1,1′-Bis(diphenylphosphino)-ferrocene]palladium(II) chloride(0.048 g, 0.07 mmol) was added and the mixture was degassed by bubblingN₂ (g) through it. The vial was sealed and heated in a microwave reactorat 130° C. for 30 min. The residue was dissolved in EtOAc and themixture was extracted with 1.0 M HCl (2×10 mL). The organic layer wasdiscarded while the aq phase was basified to pH 12 by addition of 1 MNaOH (aq). The basic water phase was extracted with DCM (2×20 mL). Theorganic phase was dried through a phase separator and concentrated invacuo. The crude product was purified by flash chromatography (0-10% 0.1M NH₃ in McOH, in DCM, 25 g SiO₂ column). The product was purified by asecond flash chromatography (0-100% EtOAc in heptane, 25 g SiO₂ column)followed by preparative chromatography. The fractions containing pureproduct were combined and concentrated. DCM was added and the organicphase was collected and dried through a phase separator and concentratedin vacuo, yielding the title compound (10 mg, 0.028 mmol, 8% yield): ¹HNMR (500 MHz, CD₃OD) δ ppm 0.14-0.23 (m, 1H), 0.50-0.58 (m, 1H),0.62-0.70 (m, 1H), 0.80 (ddd, 1H), 2.30 (s, 3H), 2.96 (d, 1H), 3.49 (d,1H), 7.02-7.08 (m, 1H), 7.47 (d, 1H), 7.59 (dd, 1H), 7.73 (s, 1H), 7.88(s, 2H); MS (MM-ES+APCI)+ m/z 361 [M+H]⁺.

Example 79(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-6′-carbonitrileStep 1: Tert-butyl[(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-yl]carbamate

Di-tert-butyl dicarbonate (87 mg, 0.40 mmol) was added to a stirredsolution of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 100 mg, 0.27 mmol) in DMF (5 mL). Thereaction was stirred at r.t. overnight. The mixture was then partitionedbetween water (10 mL) and EtOAc (10 mL). The organic phase was washedwith brine (10 mL), dried over MgSO₄ and concentrated in vacuo to givethe title compound (112 mg, 88% yield): MS (ES−) m/z 474 [M−H]⁻. Theposition of the tBuOC(O)-group was not established with certainty.

Step 2:(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-6′-carbonitrile

A mixture of tert-butyl[(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-yl]carbamate(Example 79 step 1, 112 mg, 0.24 mmol), zinc cyanide (33 mg, 0.28 mmol)and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.01 mmol) inanhydrous DMF (2.1 mL) was irradiated at 170° C. in a microwave oven for60 min and was then left at r.t. overnight. The mixture was diluted withcone NH₃ (10 mL) and extracted with DCM (2×10 mL), dried through a phaseseparator column and concentrated in vacuo. The product was purifiedusing preparative chromatography to give the title compound (5 mg, 6%yield): 1H NMR (500 MHz, CDCl₃) δ ppm 1.16 (m, 1H) 1.34 (m, 3H) 1.66 (m,2H) 2.04 (m, 2H) 2.45 (s, 3H) 2.66 (s, 2H) 3.04-3.15 (m, 1H) 3.35 (s,3H) 7.17 (s, 1H) 7.48 (d, J=7.88 Hz, 1H) 7.63 (d, J=7.57 Hz, 1H) 8.23(br. s., 1H) MS (ES+) m/z 323 [M+H]⁺.

Example 80(1r,4r)-4-Methoxy-6′-[3-(methoxymethyl)phenyl]-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Step 4 Method B, 183 mg, 0.49 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (20 mg, 0.02 mmol) and Cs₂CO₃ (317 mg, 0.97 mmol) were placed ina microwave vial. A solution of 3-(methoxymethyl)phenylboronic acid (105mg, 0.63 mmol) in a 6:3:1 mixture of DME, water and EtOH (5 mL) wasadded, and the tube was capped and flushed with argon. The mixture washeated to 120° C. in a microwave reactor for 1 h. The reaction mixturewas filtered through a plug of diatomaceous earth and MgSO₄. Thesolvents were evaporated and the residue was purified by preparativechromatography to give 54 mg (26% yield) of the title compound: ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.94 (td, 1H), 1.12-1.31 (m, 2H), 1.43-1.52 (m,3H), 1.83 (m, 2H), 2.16 (s, 3H), 2.91-3.01 (m, 2H), 3.05-3.11 (m, 1H),3.20 (s, 3H), 3.30 (s, 3H), 4.45 (s, 2H), 6.56 (s, 2H), 6.75 (d, 1H),7.25 (m, 1H), 7.35-7.40 (m, 2H), 7.40-7.44 (m, 2H), 7.44-7.47 (m, 1H);MS (ES+) m/z 418 [M+H]⁺.

Example 81(1r,4r)-6′-[3-Fluoro-5-(methoxymethyl)phenyl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

1-Bromo-3-fluoro-5-(methoxymethyl)benzene (Intermediate 53, 139 mg, 0.63mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (177mg, 0.70 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (26 mg, 0.03 mmol) andpotassium acetate (187 mg, 1.90 mmol) were weighed into a microwavevial. 2-Me THF (2 mL) was added and the vial was flushed with argon. Themixture was heated to 100° C. in a microwave reactor for 30 min. Fromthis reaction mixture, as an assumed 0.3 M solution in dioxane, wastaken the formed2-(3-fluoro-5-(methoxymethyl)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.945 mL, 0.28 mmol). The solution was added to a mixture of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 82 mg, 0.22 mmol), sodiumtetrachloropalladate(II) (7 mg, 0.02 mmol),3-(di-tert-butylphosphino)propane-1-sulfonic acid (13 mg, 0.05 mmol),K₂CO₃ (0.33 mL, 0.65 mmol) and dioxane (2 mL) in a microwave tube. Thetube was flushed with argon and the mixture was heated to 120° C. in amicrowave reactor for 2 h. The reaction mixture was partitioned betweenEtOAc and water. The aqueous phase was extracted with EtOAc. Thecombined organic layers were washed with water and dried over MgSO₄. Itwas then treated with active charcoal for 5 min, filtered andconcentrated in vacuo. The residue was purified by HPLC to give 19 mg(20% yield) of the title compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.94(m, 1H), 1.12-1.30 (m, 2H), 1.40-1.51 (m, 3H), 1.83 (m, 2H), 2.17 (s,3H), 2.91-3.02 (m, 2H), 3.05-3.11 (m, 1H), 3.20 (s, 3H), 3.31 (s, 3H),4.46 (s, 2H), 6.56 (hr. s., 2H), 6.79 (s, 1H), 7.07 (d, 1H), 7.23-7.30(m, 2H), 7.38 (d, 1H), 7.47-7.51 (m, 1H); MS (ES+) m/z 436 [M+H]⁺.

Example 82(1r,4r)-4-Methoxy-5″-methyl-6′-{5-[(2,2,2-trifluoroethoxy)methyl]pyridin-3-yl}-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (37 mg, 19% yield) was prepared as described forExample 81 starting from3-bromo-5-((2,2,2-trifluoroethoxy)methyl)pyridine (Intermediate 54, 222mg, 0.82 mmol) and(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 149 mg, 0.40 mmol): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.91-1.01 (m, 1H), 1.13-1.31 (m, 2H), 1.44-1.52 (m, 3H),1.83 (m, 2H), 2.17 (s, 3H), 2.90-3.04 (m, 2H), 3.05-3.14 (m, 1H), 3.20(s, 3H), 4.16 (q, 2H), 4.76 (s, 2H), 6.56 (s, 2H), 6.80-6.85 (m, 1H),7.42 (d, 1H), 7.50-7.56 (m, 1H), 7.83-7.90 (m, 1H), 8.48-8.52 (m, 1H),8.70 (m, 1H); MS (ES+) m/z 487 [M+H]⁺.

Example 83(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-(5-methylpyridin-3-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,1′R,4R)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 130 mg,0.21 mmol) was treated with 2-methyl-tetrahydrofuran (3 mL). Aq. KOHsolution (1 M, 3 mL) was added, and the mixture was stirred for 1 h. Thewater phase was removed and the suspension was washed with aq. K₂CO₃solution (2 M, 3 mL). The phases were separated, and to the organiclayer was added to a mixture of (5-methyl-3-pyridinyl)-boronic acid(40.5 mg, 0.30 mmol), sodium tetrachloropalladate(II) (8.80 mg, 0.03mmol), and 3-(di-tert-butylphosphonium)propane sulfonate (16.05 mg, 0.06mmol) in a microwave vial. K₂CO₃ (2.0 M, 0.320 mL, 0.64 mmol) was added,the vial was closed, and the atmosphere was exchanged for argon. Thereaction mixture was heated to 100° C. for 30 min by microwaveirradiation. The reaction mixture was cooled to r.t., diluted withEtOAc, and washed with brine. The organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified bypreparative chromatography to give the title compound (18 mg, 19%yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (td, 1H) 1.12-1.29 (m, 2H)1.41-1.52 (m, 3H) 1.83 (d, 2H) 2.17 (s, 3H) 2.33 (s, 3H) 2.89-2.98 (m,1H) 3.04 (q, 2H) 3.20 (s, 3H) 6.55 (br. s., 2H) 6.80 (s, 1H) 7.40 (d,1H) 7.50 (dd, 1H) 7.72 (s, 1H) 8.35 (s, 1H) 8.52 (d, 1H); MS (ES+) m/z389 [M+H]⁺.

Example 84(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (35 mg 32% yield) was prepared as described forExample 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 130 mg,0.21 mmol), and 5-trifluoromethyl-pyridine-3-boronic acid (56.5 mg, 0.30mmol): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87-1.06 (m, 1H) 1.11-1.31 (m,2H) 1.38-1.54 (m, 3H) 1.83 (d, 2H) 2.17 (s, 3H) 2.96 (m, 1H) 3.06 (q,2H) 3.20 (s, 3H) 6.55 (br. s, 2H) 6.93 (d, 1H) 7.45 (d, 1H) 7.63 (dd,1H) 8.28 (s, 1H) 8.91 (d, 1H) 9.05 (d, 1H); MS (ES+) m/z 443 [M+H]⁺.

Example 853-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-(trifluoromethyl)benzonitrile

The title compound (34 mg, 34% yield) was prepared as described inExample 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 130 mg,0.21 mmol)) and3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzonitrile(Intermediate 55, 70 mg, 0.23 mmol): ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.97 (br. s., 1H) 1.12-1.29 (m, 2H) 1.40-1.50 (m, 3H) 1.83 (d, 2H) 2.18(s, 3H) 2.91-3.13 (m, 3H) 3.20 (s, 3H) 6.55 (br. s., 2H) 6.94 (s, 1H)7.44 (m, 1H) 7.64 (m, 1H) 8.14 (s, 1H) 8.27 (s, 1H) 8.35 (s, 1H); MS(ES+) m/z 467 [M+H]⁺.

Example 863-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-(difluoromethyl)benzonitrile

The title compound (50 mg, 49% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 130 mg,0.21 mmol) and3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 56, 71.5 mg, 0.26 mmol): ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.96 (d, 1H) 1.19-1.30 (m, 2H) 1.38-1.50 (m, 3H) 1.83 (d, 2H) 2.18 (s,3H) 2.91-3.12 (m, 3H) 3.20 (s, 3H) 6.55 (br. s., 2H) 6.89 (d, 1H)7.01-7.26 (m, 1H) 7.43 (d, 1H) 7.60 (dd, 1H) 8.01 (d, 2H) 8.22 (s, 1H);MS (ES+) m/z 449 [M+H]′ and (ES−) m/z 447 [M−H]⁻.

Example 875-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-2-fluoro-3-methoxybenzonitrile

The title compound (13 mg, 12% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 0.150 g,0.25 mmol) and2-fluoro-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 79, 0.082 g, 0.30 mmol) except that the reaction time was1 h: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (td, 1H), 1.22 (m, 2H), 1.43(m, 3H), 1.83 (d, 2H), 2.17 (s, 3H), 2.95 (m, 2H), 3.08 (d, 1H), 3.20(s, 3H), 3.97 (s, 3H), 6.53 (s, 2H), 6.84 (d, 1H), 7.40 (d, 1H), 7.54(m, 2H), 7.58 (dd, 1H); MS (APCI+) m/z 447.2 [M+H]⁺.

Example 88(1r,1′R,4R)-6′-(3,5-difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (49 mg, 48% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 153 mg,0.25 mmol) and 3,5-difluorophenylboronic acid (48 mg, 0.30 mmol) exceptthat the reaction temperature was 120° C.: ¹H NMR (500 MHz, DMSO-d₆) δppm 1.0 (td, 1H), 1.1-1.3 (m, 2H), 1.4-1.5 (m, 3H), 1.8 (m, 2H), 2.2 (s,3H), 2.9-3.0 (m, 2H), 3.0-3.1 (m, 1H), 3.2 (s, 3H), 6.5 (s, 2H), 6.8 (s,1H), 7.1-7.2 (m, 1H), 7.2-7.3 (m, 2H), 7.4 (d, 1H), 7.5-7.6 (m, 1H); MS(ES+) m/z 410 [M+H]⁺.

Example 89(1r,1′R,4R)-6′-(2-Fluoro-3-methoxyphenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (49 mg, 47% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 153 mg,0.25 mmol) and2-(2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76mg, 0.30 mmol): ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (td, 1H), 1.10-1.33(m, 2H), 1.39-1.54 (m, 3H), 1.83 (m, 2H), 2.15 (s, 3H), 2.90-3.03 (m,2H), 3.04-3.13 (m, 1H), 3.20 (s, 3H), 3.84 (s, 3H), 6.55 (s, 2H), 6.64(s, 1H), 6.89 (td, 1H), 7.08-7.19 (m, 2H), 7.31 (m, 1H), 7.38 (d, 1H);MS (ES+) m/z 422 [M+H]⁺.

Example 90(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-phenyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (41 mg, 44% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 149 mg,0.24 mmol) and phenylboronic acid (30+6 mg, 0.24+0.05 mmol), except thatthe reaction time was 30+15 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.95(td, 1H) 1.12-1.30 (m, 2H) 1.43-1.51 (m, 3H) 1.83 (d, 2H) 2.16 (s, 3H)2.91-2.96 (m, 1H) 2.96-3.00 (m, 1H) 3.06-3.10 (m, 1H) 3.20 (s, 3H) 6.54(br. s., 2H) 6.75 (d, 1H) 7.28-7.33 (m, 1H) 7.35-7.47 (m, 4H) 7.47-7.52(m, 2H); MS (ES+) m/z 374 [M+H]⁺.

Example 913-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methoxybenzonitrile

A mixture of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 87 mg, 0.23 mmol),3-cyano-5-methoxyphenylboronic acid (45 mg, 0.25 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (17 mg,0.02 mmol), K₂CO₃ (2 M aq. solution, 0.231 mL, 0.46 mmol) and1,4-dioxane (2 mL) were mixed in a vial and heated in a microwavereactor at 130° C. for 20 min. When cooled to r.t. the mixture wasdiluted with DCM, washed with water, dried over Na₂SO₄, and concentratedin vacuo. The product was purified by preparative chromatography to givethe title compound (37 mg, 37% yield): ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.97 (m, 1H), 1.22 (m, 2H), 1.44 (m, 3H), 1.83 (d, 2H), 2.18 (s, 3H),2.99 (m, 3H), 3.19 (s, 3H), 3.85 (s, 3H), 6.83 (d, 1H), 7.37 (m, 3H),7.54 (m, 2H), 8.18 (s, 1H); MS (ES+) m/z 430 [M+H]⁺.

Example 92 Separation of the isomers of3-[(1r,4r)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methoxybenzonitrile

The racemic mixture of3-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methoxybenzonitrilefrom Example 91 (19 mg, 0.04 mmol) was separated using a SFC BergerMultigram II system with a Chiralcel OD-H column (4.6*250 mm; 5 μm) anda mobile phase consisting of 25% MeOH (containing 0.1% DEA) and 75% CO₂at a flowrate of 50 mL/min to give:

Isomer 1:3-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methoxybenzonitrile(2 mg 10% yield) with retention time 3.5 min:

¹H NMR (500 MHz, CDCl₃) δ ppm 1.04 (td, 1H), 1.29 (m, 2H), 1.42 (td,1H), 1.63 (m, 2H), 1.89 (d, 2H), 2.25 (s, 3H), 3.01 (m, 1H), 3.14 (m,2H), 3.27 (s, 3H), 3.78 (s, 3H), 6.80 (s, 1H), 6.98 (s, 1H), 7.16 (m,1H), 7.29 (s, 1H), 7.33 (s, 2H); MS (MM-ES+APCI)+ m/z 429 [M+H]⁺; and

Isomer 2:3-[(1r,1′S,4S)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methoxybenzonitrile(1 mg, 5% yield) with retention time 9.5 min:

¹H NMR (500 MHz, CDCl₃) δ ppm 1.05 (m, 1H), 1.29 (m, 3H), 1.43 (m, 1H),1.63 (m, 2H), 1.89 (d, 2H), 2.25 (s, 3H), 3.00 (m, 1H), 3.14 (m, 2H),3.27 (s, 3H), 3.78 (s, 3H), 6.80 (s, 1H), 6.98 (s, 1H), 7.16 (s, 1H),7.29 (s, 1H), 7.33 (s, 2H); MS (MM-ES+APCI)+ m/z 429 [M+H]⁺.

Example 92 Isomer 1 (Alternative Method)3-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methoxybenzonitrile

The title compound (26 mg, 24% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 151 mg,0.25 mmol) and 3-cyano-5-methoxyphenylboronic acid (44 mg, 0.25 mmol),except that the reaction time was 30+30 min: ¹H NMR (500 MHz, CDCl₃) δppm 1.16 (td, 1H), 1.42 (m, 3H), 1.74 (m, 2H), 2.02 (m, 2H), 2.39 (s,3H), 3.11 (m, 1H), 3.25 (q, 2H), 3.37 (s, 3H), 3.88 (s, 3H), 6.93 (s,1H), 7.09 (s, 1H), 7.26 (m, 1H), 7.39 (s, 1H), 7.46 (m, 2H); MS(MM-ES+APCI)+ m/z 429 [M+H]⁺.

Example 933-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-bromobenzonitrile

A mixture of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 120 mg, 0.32 mmol), potassium acetate (63mg, 0.64 mmol), bis(pinacolato)diboron (89 mg, 0.35 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (13 mg, 0.02 mmol) in dioxane (2 mL) weremixed in a vial and heated in a microwave reactor at 130° C. for 35 min.Formation of(1r,4r)-4-methoxy-5″-methyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-aminewas observed by LCMS (MS (ES+) m/z 342, 425 [M+H]⁺, masses correspondingto both the boronic ester and the hydrolysed boronic acid weredetected). The obtained mixture was used as is. K₂CO₃ (2 M aq. solution,0.319 mL, 0.64 mmol), Pd(Ph₃P)₄ (18 mg, 0.02 mmol) and3,5-dibromobenzonitrile (125 mg, 0.48 mmol) in dioxane (1 mL) were addedto the above mixture containing(1r,4r)-4-methoxy-5″-methyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine.The reaction vessel was sealed and heated in a microwave reactor at 130°C. for 20 min. When cooled to r.t. the mixture was diluted with DCM,washed with brine, dried over MgSO₄, and concentrated in vacuo. Theproduct was purified by preparative chromatography to give the titlecompound (45 mg, 30% yield): ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97 (m,1H), 1.21 (m, 2H), 1.44 (m, 3H), 1.83 (d, 2H), 2.18 (s, 3H), 2.94 (m,1H), 3.00 (d, 1H), 3.09 (d, 1H), 3.20 (s, 3H), 6.56 (br. s., 1H), 6.88(d, 1H), 7.41 (d, 1H), 7.58 (dd, 1H), 8.07 (m, 3H); MS (ES+) m/z 477[M+H]⁺.

Example 94 Separation of the isomers of3-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-bromobenzonitrile

The racemic mixture of3-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-bromobenzonitrilefrom Example 93 (60 mg, 0.13 mmol) was separated using a SFC BergerMultigram II system with a Chiralcel OD-H column (20*250 mm; 5 μm) and amobile phase consisting of 35% MeOH (containing 0.1% DEA) and 65% CO₂ ata flowrate of 50 mL/min to give

Isomer 1 with undetermined absolute configuration (13 mg, 22% yield)with retention time 2.0 min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.12 (td,1H), 1.37 (m, 2H), 1.50 (m, 1H), 1.70 (m, 2H), 1.97 (d, 2H), 2.34 (s,3H), 3.08 (m, 1H), 3.22 (m, 2H), 3.35 (s, 3H), 6.87 (m, 1H), 7.41 (m,2H), 7.70 (dt, 2H), 7.87 (t, 1H); MS (MM-ES+APCI)+ m/z 477 [M+H]⁺; and

Isomer 2 with undetermined absolute configuration (15 mg, 25% yield)with retention time 4.9 Min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.12 (td,1H), 1.38 (m, 2H), 1.51 (td, 1H), 1.70 (m, 2H), 1.97 (d, 2H), 2.34 (s,3H), 3.09 (t, 1H), 3.23 (m, 2H), 3.35 (s, 3H), 6.87 (s, 1H), 7.41 (m,2H), 7.70 (m, 2H), 7.87 (t, 1H); MS (MM-ES+APCI)+ m/z 477 [M+H]⁺.

Example 953-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-ethylbenzonitrile

The title compound (38 mg, 17% yield) was prepared as described forExample 93 starting from 3-bromo-5-ethylbenzonitrile (Intermediate 58,0.124 g, 0.59 mmol) and(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine)(Example 19 Method B Step 4, 200 mg, 0.53 mmol): ¹H NMR (400 MHz, CDCl₃)δ ppm 1.14 (td, 1H) 1.27 (t, 3H) 1.36 (m, 3H) 1.71 (m, 2H) 2.00 (m, 2H)2.39 (s, 3H) 2.72 (q, 2H) 3.10 (m, 1H) 3.23 (m, 2H) 3.35 (s, 3H) 6.95(m, 1H) 7.45 (m, 3H) 7.54 (s, 1H) 7.59 (m, 1H) 8.49 (s, 1H); MS (ES+)m/z 427 [M+H]⁺.

Example 963-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-(methoxymethyl)benzonitrile

The title compound (52 mg, 40% yield) was prepared as described forExample 93 starting from 3-bromo-5-(methoxymethyl)benzonitrile(Intermediate 59, 66 mg, 0.29 mmol) and(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine)(Example 19 Method B Step 4, 109 mg, 0.29 mmol): ¹H NMR (500 MHz, CDCl₃)δ ppm 1.15 (td, 1H), 1.39 (m, 3H), 1.72 (m, 2H), 2.02 (m, 2H), 2.43 (s,3H), 3.10 (m, 1H), 3.20 (d, 1H), 3.28 (d, 1H), 3.35 (s, 3H), 3.44 (s,3H), 4.52 (s, 2H), 6.99 (s, 1H), 7.48 (m, 2H), 7.58 (s, 1H), 7.69 (d,2H), 8.41 (br. s., 1H); MS (MM-ES+APCI)+ m/z 443 [M+H]⁺.

Example 97 Separation of the isomers of3-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-(methoxymethyl)benzonitrile

The racemic mixture from Example 96 (40 mg, 0.09 mmol) was separatedusing a SFC_Berger Multigram II system with a Chiralcel OD-H column(20*250 mm; 5 μm) and a mobile phase consisting of 30% MeOH (containing0.1% DEA) and 70% CO₂ at a flow rate of 50 mL/min to give:

Isomer 1 with undetermined absolute configuration (14 mg, 35% yield)with retention time 2.5 min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.12 (td,1H), 1.37 (m, 2H), 1.51 (td, 1H), 1.72 (td, 2H), 1.97 (d, 2H), 2.34 (s,3H), 3.09 (m, 1H), 3.23 (m, 2H), 3.35 (s, 3H), 3.43 (s, 3H), 4.50 (s,2H), 6.91 (s, 1H), 7.43 (m, 2H), 7.54 (s, 1H), 7.70 (s, 2H); MS(MM-ES+APCI)+ m/z 443 [M+H]⁺; and

Isomer 2 with undetermined absolute configuration (13 mg, 33% yield)with retention time 7.5 min: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.12 (td,1H), 1.38 (m, 2H), 1.51 (m, 1H), 1.72 (m, 2H), 1.97 (d, 2H), 2.34 (s,3H), 3.09 (m, 1H), 3.23 (m, 2H), 3.35 (s, 3H), 3.43 (s, 3H), 4.50 (s,2H), 6.91 (s, 1H), 7.43 (m, 2H), 7.54 (s, 1H), 7.70 (s, 2H); MS(MM-ES+APCI)+ m/z 443 [M+H]⁺.

Example 98(1r,1′R,4R)-6′-(2-Fluoro-5-methoxyphenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound was prepared according to the procedure described inExample 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 150 mg,0.25 mmol) and 2-fluoro-5-methoxyphenylboronic acid (42+21 mg, 0.25mmol), except that the reaction time was 30+30 min. The resultingmaterial was combined with a product from an identical reaction runstarting with 80 mg (0.13 mmol) of(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt and purified by preparativechromatography to afford 38 mg (24% yield) of the title compound: ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.94 (m, 1H) 1.21 (m, 2H) 1.47 (m, 3H) 1.83 (m,2H) 2.15 (s, 3H) 2.94 (m, 1H) 3.04 (m, 2H) 3.20 (s, 3H) 3.76 (s, 3H)6.54 (s, 2H) 6.67 (s, 1H) 6.88 (m, 2H) 7.17 (t, 1H) 7.36 (m, 2H); MS(ES+) m/z 422 [M+H]⁺.

Example 99(1r,1′R,4R)-6′-(2,5-Difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (24.4 mg, 16% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 230 mg,0.38 mmol) and 2,5-difluorophenylboronic acid (87 mg, 0.56 mmol): ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.94 (m, 1H) 1.21 (m, 2H) 1.46 (m, 3H) 1.83 (m,2H) 2.15 (s, 3H) 2.94 (m, 1H) 3.05 (dd, 2H) 3.20 (s, 3H) 6.54 (s, 2H)6.70 (s, 1H) 7.20 (m, 1H) 7.29 (m, 2H) 7.38 (d, 2H); MS (ES+) m/z 410[M+H]⁺.

Example 1005-[(1r,1′R,4R)-4″-amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-3-chloro-2-fluorobenzonitrile

The title compound (22 mg, 20% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 150 mg,0.25 mmol) and3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 57, 90 mg, 0.32 mmol): ¹H NMR (500 MHz, CDCl₃) δ ppm1.07-1.17 (m, 1H), 1.29-1.44 (m, 3H), 1.50 (br. s., 2H), 1.65-1.75 (m,4H), 1.98 (d 2H), 2.36 (s, 3H), 3.04-3.13 (m, 1H), 3.23 (d, 2H), 3.35(s, 3H), 6.85 (d, 1H), 7.35-7.39 (m, 1H), 7.41-7.45 (m, 1H), 7.63 (dd,1H), 7.77 (dd, 2.36 Hz, 1H); MS (ES+) m/z 451 [M+H]⁺.

Example 101(1r,1′R,4R)-6′-(2,3-Difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 150 mg,0.40 mmol) was treated with 2-Me THF (2 mL) and aq. KOH solution (0.4 gKOH in 3 mL water). The reaction was stirred for 30 min before the waterphase was removed and the remaining suspension was washed with 2 M aq.Na₂CO₃ solution (3 mL). The water solution was removed, and the organicphase was transferred to a microwave vial. 2,3-difluorophenylboronicacid (126 mg, 0.80 mmol) was added, followed by Na₂CO₃ (598 μL, 1.20mmol). The solution was degassed by bubbling argon through it.1,1′-Bis(diphenylphosphino)ferrocene-palladium dichloride (16.4 mg, 0.02mmol) was added, and the reaction was irradiated in the microwavereactor for 30 min at 120° C. Water/EtOAc was added, the phases wereseparated. The organic phase was washed with brine and water and driedover Na₂SO₄ and then concentrated in vacuo. The product was purifiedusing preparative chromatography to give the title compound (61 mg, 60%yield): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.14 (d, 1H) 1.42 (d, 3H)1.67-1.81 (m, 2H) 1.94-2.12 (m, 2H) 2.41 (s, 3H) 3.11 (m, 1H) 3.16 20(m, 1H) 3.29 (m, 1H) 3.36 (s, 3H) 6.97 (s, 1H) 7.06-7.15 (m, 3H) 7.44(m, 1H) 7.50 (m, 1H) 8.35 (s, 1H); MS (ES+) m/z 410 [M+H]⁺.

Example 1023-[(1r,1′R,4R)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-4-fluorobenzonitrile

The title compound (20 mg, 19% yield) was prepared using the proceduredescribed in Example 101 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 150 mg,0.40 mmol) and 5-cyano-2-fluorophenylboronic acid (131 mg, 0.80 mmol):¹H NMR (500 MHz, CDCl₃) δ ppm 1.15 (td, 1H) 1.31-1.47 (m, 3H) 1.67-1.79(m, 2H) 1.95-2.11 (m, 2H) 2.43 (s, 3H) 3.12 (m, 1H) 3.22 (m, 1H) 3.30(m, 1H) 3.36 (s, 3H) 6.95 (s, 1H) 7.23 (dd, 1H) 7.41-7.52 (m, 2H) 7.61(ddd, 1H) 7.70 (dd, 1H) 8.38 (br. s., 1H); MS (ES+) m/z 417 [M+H]⁺.

Example 103(1r,1′R,4R)-6′-(2,4-Difluorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (56 mg, 53% yield) was prepared according to theprocedure described in Example 83 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 155 mg,0.25 mmol) and 2,4-difluorophenylboronic acid (48.3 mg, 0.31 mmol). Thetitle compound was recrystallized from CHCl₃/MeOH: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.95 (m, 1H), 1.12-1.32 (m, 2H), 1.39-1.55 (m, 3H), 1.84(d, 2H), 2.16 (s, 3H), 2.91-3.01 (m, 2H), 3.11 (d, 1H), 3.21 (s, 3H),6.55 (s, 2H), 6.65 (s, 1H), 7.14 (td, 1H), 7.26-7.35 (m, 2H), 7.40 (d,1H), 7.45 (m, 1H); MS (ES+) m/z 410.1 [M+H]⁺.

Example 104(1r,1′R,4R)-6′-(2,3-dichlorophenyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (19 mg, 11% yield) was prepared using the proceduredescribed in Example 101 starting from(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 150 mg,0.40 mmol) and 2,3-dichlorophenylboronic acid (114 mg, 0.60 mmol): ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.01 (m, 1H) 1.13-1.34 (m, 2H) 1.41 (t, 1H)1.49 (d, 2H) 1.84 (d, 2H) 2.17 (s, 3H) 2.95 (m, 1H) 3.03 (m, 1H) 3.12(m, 1H) 3.20 (s, 3H) 6.61 (s, 1H) 7.25 (dd, 2H) 7.35-7.41 (m, 2H) 7.61(dd, 1H); MS (ES+) m/z 442 [M+H]⁺.

Example 1053-[(1r,4r)-4″-Amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-fluorobenzonitrile

3-Cyano-5-fluorophenylboronic acid (54 mg, 0.33 mmol) was added to(1r,4r)-6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 15 Step 3, 90 mg, 0.22 mmol) in dry 2-methyl-tetrahydrofuran (2mL). K₂CO₃ (2.0 M aq., 0.327 mL, 0.65 mmol) was added. The mixture wasdegassed by bubbling Ar (g) through it (1 min). Then sodiumtetrachloropalladate(II) (3.2 mg, 10.92 μmol) and3-(di-tert-butylphosphonium)propane sulfonate (5.9 mg, 0.02 mmol) wereadded and the mixture was microwaved for 40 min at 100° C.3-Cyano-5-fluorophenylboronic acid (54 mg, 0.33 mmol), sodiumtetrachloropalladate(II) (3.2 mg, 10.92 μmol) and3-(di-tert-butylphosphonium)propane sulfonate (5.9 mg, 0.02 mmol) wereadded and the mixture was microwaved for 1 h at 120° C. Water,2-methyl-tetrahydrofuran and EtOAc were added to the mixture and thephases were separated. The organic phase was washed once with brine andwater. The organic phase was dried (Na₂SO₄), filtered and concentratedin vacuo. Purification by flash chromatography using a gradient ofCHCl₃/MeOH (30:1-20:1) followed by preparative chromatography gave thetitle compound (13 mg, 13% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.05(m, 1H), 1.37-1.58 (m, 5H), 1.81 (d, 2H), 2.19 (s, 3H), 3.03 (d, 1H),3.12 (d, 1H), 3.88 (m, 1H), 6.56 (s, 2H), 6.66 (t, 1H), 6.91 (s, 1H),7.42 (d, 1H), 7.60 (dd, 1H), 7.79 (m, 2H), 7.91 (s, 1H); MS (ES+) m/z453.0 [M+H]⁺.

Example 1063-[(1r,4r)-4″-Amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-methoxybenzonitrile

The title compound (45 mg, 22% yield) was prepared using the proceduredescribed in Example 105 starting from3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(139+139 mg, 0.54+0.54 mmol) and(1r,4r)-6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro-[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 15 Step 3, 184 mg, 0.45 mmol). The reaction mixture was run ina microwave reactor at 100° C. for 40 min followed by a total of 3 h at120° C.: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.04 (m, 1H), 1.38-1.58 (m,5H), 1.81 (m, 2H), 2.18 (s, 3H), 3.02 (d, 1H), 3.12 (d, 1H), 3.81-3.93(m, 4H), 6.56 (s, 2H), 6.66 (t, 1H), 6.83 (d, 1H), 7.33-7.43 (m, 3H),7.50-7.59 (m, 2H); MS (ES+) m/z 465.1 [M+H]⁺.

Example 107(1r,4r)-4-(Difluoromethoxy)-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (68.5 mg, 59% yield) was prepared using the proceduredescribed in Example 105 starting from3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine(99+99 mg, 0.36+0.36 mmol) and(1r,4r)-6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 15 Step 3, 100 mg, 0.24 mmol). The reaction was heated in amicrowave reactor at 120° C. for 40+30 min: ¹H NMR (500 MHz, DMSO-d₆) δppm 0.96-1.11 (m, 1H), 1.39-1.47 (m, 1H), 1.47-1.60 (m, 4H), 1.82 (m,2H), 2.18 (s, 3H), 3.05 (d, 1H), 3.14 (d, 1H), 3.89 (m, 1H), 6.58 (br.s., 2H), 6.66 (t, 1H), 6.94 (d, 1H), 7.46 (d, 1H), 7.64 (dd, 1H), 8.28(s, 1H), 8.91 (s, 1H), 9.05 (d, 1H); MS (ES+) m/z 479.1 [M+H]⁺.

Example 1083-[(1r,4r)-4″-Amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-chlorobenzonitrile

The title compound (20 mg, 17% yield) was prepared using the proceduredescribed in Example 105 starting from3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 35, 96 mg, 0.36 mmol) and(1r,4r)-6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 15 Step 3, 100 mg, 0.24 mmol). The reaction was heated in amicrowave reactor at 120° C. for 40+30+30 min: ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.05 (m, 1H), 1.38-1.57 (m, 5H), 1.81 (m, 2H), 2.19 (s, 3H), 3.03(d, 1H), 3.12 (d, 1H), 3.88 (m, 1H), 6.56 (s, 2H), 6.66 (t, 1H), 6.90(s, 1H), 7.42 (d, 1H), 7.59 (dd, 1H), 7.95 (m, 2H), 8.02 (s, 1H); MS(ES+) m/z 469.1 [M+H]⁺.

Example 109(1r,4r)-4-(Difluoromethoxy)-6′-(3,5-difluorophenyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound was prepared using the procedure described in Example105 starting from2-(3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (62+34+34mg, 0.26+0.14+0.14 mmol) and(1r,4r)-6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 15 Step 3, 97 mg, 0.24 mmol). The reaction was heated in amicrowave reactor at 120° C. for respectively 30+30+20 min. Purificationby preparative chromatography (2 separate injections) using a XBridgeC18; 21*250 mm; 5 μM column and 40-80% MeCN/0.1% aq. NH₃ as mobile phasewith a flow rate of 20 mL/min gave the title compound with retentiontime 12.4 min. The desired fractions were pooled, the acetonitrile wasevaporated and the remaining aqueous phase was extracted with DCM. Theorganic layer was washed with water, concentrated and dried in vacuo at45° C. overnight to give the title compound (44.5 mg, 42% yield): ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.98-1.08 (m, 1H) 1.40-1.46 (m, 1H) 1.46-1.56(m, 4H) 1.77-1.85 (m, 2H) 2.18 (s, 3H) 3.01 (d, 1H) 3.11 (d, 1H)3.84-3.93 (m, 1H) 6.56 (s, 2H) 6.83 (s, 1H) 7.17 (tt, 1H) 7.27 (d, 2H)7.39 (d, 1H) 7.52-7.57 (m, 1H); MS (ES+) m/z 446.0 [M+H]⁺.

Example 1105-[(1r,4r)-4″-Amino-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-2-fluoro-3-methoxybenzonitrile

The title compound (22 mg, 21% yield) was prepared using the proceduredescribed in Example 105 starting from2-fluoro-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 79, 89+30 mg, 0.32+011 mmol) and(1r,4r)-6′-bromo-4-(difluoromethoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 15 Step 3, 88 mg, 0.21 mmol). The reaction mixture was heatedwith MW at 120° C. for 30+30+15 min. Purification by preparativechromatography (3 separate injections) using a XBridge C18; 4.6*250 mm;5 μm column and 30-70% MeCN/0.1% aqueous NH₃ as mobile phase with a flowrate of 20 mL/min gave the title compound with retention time 16.2 min:¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98-1.08 (m, 1H) 1.40-1.55 (m, 5H)1.76-1.86 (m, 2H) 2.18 (s, 3H) 3.02 (d, 1H) 3.11 (d, 1H) 3.83-3.93 (m,1H) 3.97 (s, 3H) 6.56 (s, 2H) 6.66 (t, 1H) 6.85 (s, 1H) 7.41 (d, 1H)7.53-7.57 (m, 2H) 7.58 (dd, 1H); MS (ES+) m/z 483.0 [M+H]⁺.

Example 111(1r,4r)-4-Methoxy-4,5″-dimethyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazo]-4″-amineStep 1:N-[(1r,4r)-6′-Bromo-4-methoxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-ylidene]-2-methylpropane-2-sulfinamide

(1r,4r)-6′-Bromo-4-methoxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 61, 0.613 g, 1.90 mmol), 2-methylpropane-2-sulfinamide(0.919 g, 7.59 mmol) and titanium(IV) ethoxide (2.163 mL, 10.43 mmol)were dissolved in 2-Me THF (6 mL) and heated at reflux for 6 days. Thereaction was allowed to cool to r.t. and thereafter it was diluted withEtOAc (30 mL). Water (20 mL) was added under vigorous stirring, and theobtained mixture was stirred for 10 min. Diatomaceous earth was addedand the mixture was left standing without stirring for 1 h. The mixturewas filtered through a pad of diatomaceous earth. The organic layer wasseparated, dried over MgSO₄ and concentrated in vacuo. The crude titlecompound (0.7 g, 87% yield) was used in the next step without furtherpurification: MS (ES+) m/z 428 [M+H]⁺.

Step 2:(1r,4r)-6′-Bromo-4-methoxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4M in 1,4-dioxane, 1.9 mL, 7.60 mmol) was added to a solution ofN-((1r,4r))-5′-bromo-4-methoxy-4-methylspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(0.648 g, 1.52 mmol, Example 111 Step 1) in anhydrous 1,4-dioxane (4 mL)and the resulting mixture was stirred under a nitrogen atmosphere atr.t. for 90 min. A precipitate was formed. Et₂O (5 mL) was added and thesolid was filtered off and washed with Et₂O (5 mL). The solid waspartitioned between DCM (20 mL) and sat. aq. NaHCO₃ (20 mL). The phaseswere separated, the organic layer dried over Na₂SO₄ and concentrated invacuo to yield the crude title compound that was used directly in thenext step: GCMS (CI) m/z 322 [M+H]⁺.

Step 3:(1r,4r)-6′-Bromo-4-methoxy-4,5″-dimethyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

(1r,4r)-6′-Bromo-4-methoxy-4-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(0.515 g, 1.60 mmol, Example 111 Step 2) and 2-oxopropanethioamide(Intermediate 2, 0.495 g, 4.79 mmol) were dissolved in MeOH (6 mL) andrefluxed for 18 h. The reaction was concentrated and the residue wasdissolved in DCM (10 mL). The organic layer was washed with water (10mL), dried over Na₂SO₄, and filtered. The filtrate was passed through apad of silica gel and eluted with DCM (removal of side products) andwith DCM:MeOH (9:1) (to elute the product). The product solution wasconcentrated to give the title compound (0.536 g, 82% yield): ¹H NMR(500 MHz, CDCl₃) δ ppm 1.16 (s, 3H), 1.35 (m, 3H), 1.60 (m, 8H), 2.40(s, 3H), 3.08 (s, 2H), 3.23 (s, 3H), 7.06 (d, 1H), 7.20 (d, 1H), 7.45(dd, 1H); MS (ES+) m/z 407 [M+H]⁺.

Step 4:(1r,4r)-6′-Bromo-4-methoxy-4,5″-dimethyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-4,5″-dimethyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(0.535 g, 1.31 mmol Example 111 Step 3) was dissolved in ammonia (7 M inMeOH, 16.89 mL, 118.2 mmol) and the mixture was heated with microwavesat 90° C. for 60 min. The mixture was concentrated, dissolved in ammonia(7M in MeOH, 18.76 ml, 131.3 mmol) and it was heated again withmicrowaves for 30 min at 90° C. This procedure (concentration andammonia treatment in microwave reactor) was repeated once more. Themixture was concentrated and the product purified by flashchromatography with a gradient of 0-6% MeOH in DCM (containing 6% 7N NH₃in MeOH): ¹H NMR (500 MHz, CDCl₃) δ ppm 1.12 (s, 3H), 1.56 (m, 8H), 2.32(s, 3H), 3.11 (d, 2H), 3.22 (s, 3H), 6.84 (d, 1H), 7.17 (d, 1H), 7.33(dd, 1H); MS (ES+) m/z 392 [M+H]⁺.

Step 5:(1r,4r)-4-Methoxy-4,5″-dimethyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

A mixture of(1r,4r)-6′-bromo-4-methoxy-4,5″-dimethyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 111, Step 4, 84 mg, 0.22 mmol),5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 45 mg, 0.28mmol) [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) chloride(17.7 mg, 0.02 mmol), K₂CO₃ (2 M aq. solution, 0.215 mL, 0.43 mmol) and1,4-dioxane (1 mL) was heated in a microwave reactor at 130° C. for 20min. When cooled to r.t. the mixture was diluted with DCM, washed withwater, dried over Na₂SO₄ and concentrated in vacuo. The product waspurified by preparative chromatography to give the title compound (53mg, 58% yield): ¹H NMR (CDCl₃) δ ppm 1.15 (s, 3H), 1.29 (d, 1H), 1.65(m, 7H), 2.10 (s, 3H), 2.39 (s, 3H), 3.20 (m, 1H), 3.24 (s, 3H), 3.27(m, 1H), 6.94 (d, 1H), 7.45 (m, 2H), 7.78 (t, 1H), 8.55 (d, 1H), 8.62(d, 1H); MS (MM-ES+APCI)+ m/z 427 [M+H]⁺.

Example 112(1r,4r)-6′-(Cyclobutylethynyl)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

To a mixture of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 0.168 g, 0.45 mmol), K₂CO₃ (0.093 g, 0.67mmol), copper(I) iodide (5.10 mg, 0.03 mmol),tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.03 mmol) in DMF (10mL) was added (cyclobutylethynyl)trimethylsilane (0.102 g, 0.67 mmol)(see Kozhushkov, S. I.; Wagner-Gillen, K.; Khlebnikov A. F.; de Meijere,A. Synthesis 2010 (23), 3967-3973). The atmosphere over the reactionmixture was exchanged to argon and the mixture was heated to 70° C.overnight. The reaction was allowed to reach r.t. EtOAc and brine wereadded. The organic phase was dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by preparative chromatography to givethe title compound (73 mg, 44% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.28 (d, 1H), 1.49 (d, 2H), 1.70-1.83 (m, 3H), 2.10-2.21 (m, 3H),2.21-2.31 (m, 1H), 2.41 (td, 2H), 2.50 (s, 3H), 2.55-2.65 (m, 2H),3.23-3.42 (m, 3H), 3.50-3.59 (m, 4H), 6.85 (s, 1H), 6.88 (s, 2H), 7.51(dd, 1H), 7.59 (d, 1H); MS (ES+) m/z 376 [M+H]⁺.

Example 113(1r,4r)-4-Methoxy-5″-methyl-6′-(3-methylbut-1-yn-1-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

To a solution of(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 0.153 g, 0.41 mmol) in DMF (8 mL) underargon was added 3-methylbut-1-yne (0.028 g, 0.41 mmol),tetrakis(triphenylphosphine)-palladium(0) (0.047 g, 0.04 mmol) andtriethylamine (1.70 mL, 12.2 mmol). The reaction mixture was stirred atr.t. for 5 min, then cuprous iodide (0.012 g, 0.06 mmol) was added andthe reaction mixture was heated at 65° C. for 18 h. The reaction mixturewas partitioned between brine and EtOAc. The organic phase was driedover MgSO₄ and concentrated in vacuo. The residue was purified bypreparative chromatography to give the title compound (0.035 g, 24%yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87-0.98 (m, 1H), 1.09-1.26 (m,8H), 1.35-1.48 (m, 3H), 1.81 (d, 2H), 2.15 (s, 3H), 2.73 (dt, 1H),2.88-3.08 (m, 3H), 3.18 (s, 3H), 6.49 (s, 1H), 6.54 (s, 2H), 7.15 (dd,1H), 7.24 (d, 1H); MS (ES+) m/z 364 [M+H]^(|).

Example 114(1r,1′R,4R)-4-Methoxy-5″-methyl-6′-{5-[(²H₃)prop-1-yn-1-yl]pyridin-3-yl}-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

A solution of(1r,1′R,4R)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineas the D(+)-10-camphor sulfonic acid salt (Example 19 Step 5, 135 mg,0.22 mmol) in 2-Me THF (3 mL) was treated with KOH (1 M aq, 3.5 mL). Themixture was stirred for 30 min, the organic layer separated, washed withwater, dried over Na₂SO₄ and concentrated. The residue was dissolved in1,4-dioxane (2 mL) and bis(pinacolato)diboron (62 mg, 0.24 mmol),potassium acetate (44 mg, 0.44 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (9mg, 0.01 mmol) were added. The obtained mixture was heated withmicrowaves at 130° C. for 40 min. After cooling, the vessel wasuncapped, and K₂CO₃ (2 M aq, 0.22 mL, 0.44 mmol), Pd(Ph₃P)₄ (13 mg, 0.01mmol) and 3-bromo-5-[(²H₃)prop-1-yn-1-yl]pyridine (Intermediate 70, 53mg, 0.27 mmol) in dioxane (1 mL) were added. The reaction vessel wassealed and heated with microwaves at 130° C. for 20 min. The mixture wasdiluted with DCM, washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The product was purified by preparativechromatography (XBridge column 19×250 mm, 5 μm, with a mobile phase of20-60% MeCN in 0.1% aq. ammonia, at a flow rate of 15 mL/min) to yieldthe title compound (15 mg, 16% yield, retention time 14 min): ¹H NMR(500 MHz, CDCl₃) δ ppm 1.12 (td, 1H), 1.37 (m, 2H), 1.50 (m, 1H), 1.72(m, 2H), 1.98 (m, 2H), 2.34 (s, 3H), 3.09 (m, 1H), 3.23 (m, 2H), 3.35(s, 3H), 6.92 (s, 1H), 7.43 (s, 2H), 7.77 (t, 1H), 8.54 (d, 1H), 8.62(d, 1H); MS (MM-ES+APCI)+ m/z 416 [M+H]⁺.

Example 1153-(4″-Amino-5″-methyl-4-oxodispiro[cyclohexane-1,2′-[1H]indene-1′(3′H),2″-[2H]imidazol]-6′-yl)-5-fluorobenzonitrileStep 1:N-(6″-Bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-ylidene)-2-methylpropane-2-sulfinamide

6″-Bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-one(Intermediate 71, 320 mg, 0.95 mmol), 2-methylpropane-2-sulfinamide (173mg, 1.42 mmol) and titanium ethoxide (0.391 mL, 1.90 mmol) weredissolved in 2-Me THF (5 mL) and heated to reflux overnight. Thereaction was stopped and was left to cool down to r.t. EtOAc and waterwere added under stirring. The mixture was left to stand still for 2 h.The organic phase was collected by filtration, dried using a phaseseparator and concentrated in vacuo. The crude product was purified byflash chromatography using a gradient of 0-30% EtOAc in heptane to givethe title compound (290 mg, 69% yield): ¹H NMR (500 MHz, CDCl₃) δ ppm1.35 (s, 9H) 1.48-1.54 (m, 1H) 1.61 (dd, 1H) 1.67-1.77 (m, 2H) 1.81-1.90(m, 2H) 2.10 (br. s., 2H) 2.95-3.05 (m, 2H) 3.95-4.02 (m, 4H) 7.25 (s,1H) 7.60 (dd, 1H) 8.62 (br. s., 1H); MS (ES+) m/z 440.0 [M+H]⁺.

Step 2:6′-Bromo-1′-imino-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-one

ToN-(6″-bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-ylidene)-2-methylpropane-2-sulfinamide(Example 115, Step 1, 288 mg, 0.65 mmol) in 1,4-dioxane (2 mL) under N₂(g) was added HCl (4 M in 1,4-dioxane, 1.635 mL, 6.54 mmol). The mixturewas stirred at r.t overnight and was then concentrated. The crudeproduct was dissolved in DCM and was washed with NaHCO₃ (sat. aq). Theaqueous phase was extracted with DCM. The combined organics were driedusing a phase separator and concentrated to give the title compound (220mg, quantitative yield) that was used directly in the next step: ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.13-1.24 (m, 2H) 1.25-1.35 (m, 2H) 1.66-1.75(m, 2H) 1.83-1.93 (m, 2H) 2.86 (s, 2H) 5.83 (s, 1H) 7.40 (d, 1H) 7.64(dd, 1H) 7.69 (d, 1H); MS (ES+) m/z 292 [M+H]^(|).

Step 3:6′-Bromo-4″-methyl-5″-thioxo-1″,5″-dihydro-3′H,4H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-one

6′-Bromo-1′-imino-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-one(Example 115, Step 2, 2.37 g, 8.11 mmol) and trimethyl orthoformate (2.5mL, 22.8 mmol) in 2-propanol (25 mL) was heated to 80° C.2-Oxopropanethioamide (Intermediate 2, 1.673 g, 16.2 mmol) dissolved in2-propanol (10 mL) was added. The mixture was heated at 80° C.overnight. The mixture was allowed to cool to r.t. before concentrated.The crude product was purified by flash chromatography using a gradientof 0-100% EtOAc in heptane. The desired fractions were concentrated togive the title compound (0.563 g, 18% yield): ¹H NMR (500 MHz, CDCl₃) δ1.69 (ddd, 1H), 1.74-1.81 (m, 1H), 1.90-1.96 (m, 1H), 2.00-2.05 (m, 1H),2.40 (s, 4H), 2.42-2.55 (m, 3H), 3.25-3.35 (m, 2H), 7.11 (d, 1H), 7.26(br. s., 1H), 7.50 (dd, 1H), 8.67 (br. s., 1H); MS (ES+) m/z 377 [M+H]⁺.

Step 4:6″-Bromo-5′″-methyl-3″H-trispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-indene-1″,2′″-imidazole]-4′″(3′″H)-thione

Ethane-1,2-diol (0.074 mL, 1.33 mmol),6′-bromo-4″-methyl-5″-thioxo-1″,5″-dihydro-3′H,4H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-one(Example 115 Step 3, 0.5 g, 1.33 mmol) and p-toluenesulfonic acidmonohydrate (0.013 g, 0.07 mmol) in toluene (8 mL) were heated to refluxovernight. The mixture was cooled to r.t and then washed with NaHCO₃(sat aq). The aqueous phase was extracted with EtOAc. The combinedorganic phases were dried with MgSO₄, filtered and concentrated in vacuoto yield the title compound (0.506 g, 91% yield): MS [ES+] m/z 423[M+H]⁺.

Step 5:6″-Bromo-5′″-methyl-3″H-trispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-indene-1″,2′″-imidazol]-4′″-amine

6″-Bromo-5′″-methyl-3″H-trispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-indene-1″,2′″-imidazole]-4′″(3′″H)-thione(Example 115 Step 4, 0.5 g, 1.19 mmol) was taken up in ammonia (7 M inMeOH, 15 mL, 105 mmol) and the resulting mixture was heated in themicrowave reactor at 110° C. for 30 min. The solvent was evaporated invacuo and the same procedure (addition of ammonia, heating andevaporation) was repeated 3 times. The solvent was evaporated to yieldthe title compound (0.568 g, quantitative yield) that was used withoutfurther purification: ¹H NMR (500 MHz, CDCl₃) δ ppm 1.35-1.49 (m, 2H),1.61 (d, 2H), 1.69-1.81 (m, 2H), 2.33 (s, 3H), 3.14 (s, 2H), 3.87-3.98(m, 4H), 6.88 (d, 1H), 7.19 (d, 1H), 7.35 (dd, 1H); MS (ES+) m/z 404[M+H]⁺.

Step 6:4″-Amino-6′-bromo-5″-methyl-3′H,4H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-one

6″-Bromo-5′″-methyl-3″H-trispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-indene-1″,2′″-imidazol]-4′″-amine(Example 115 Step 5, 0.568 g, 1.40 mmol) was dissolved in HCl (1.25 M inMeOH, 15 mL, 18.8 mmol) and water (5 mL). The mixture was stirred at 60°C. for 1.5 h. and then at 80° C. for 3 h. EtOAc was added and theaqueous phase was extracted. The aqueous phase was discarded. Aq. citricacid solution (0.1 M) was added to the organic phase and the phases wereseparated. The organic phase was extracted once more with citric acid(0.1 M aq.). The combined citric acid phases were basified with 1 M NaOHand extracted with DCM twice. The combined organic phases were driedwith a phase separator and evaporated to dryness in vacuo. The crudeproduct was purified by flash chromatography (24 g SiO₂, gradientelution 0-20% (0.1 M NH₃ in MeOH) in DCM) to yield the title compound(0.116 g, 23% yield): ¹H NMR (500 MHz, CD₃OD) δ ppm 1.24 (t, 1H), 1.55(td, 1H), 1.88 (dd, 2H), 2.15-2.30 (m, 2H), 2.30-2.38 (m, 3H), 2.42-2.60(m, 2H), 3.27 (s, 1H), 3.33-3.41 (m, 1H), 6.88 (d, 1H), 7.31 (d, 1H),7.42 (dd, 1H); MS (MM-ES+APCI)+ m/z 360.0 [M+H]⁺.

Step 7:3-(4″-Amino-5″-methyl-4-oxodispiro[cyclohexane-1,2′-[1H]indene-1′(3′H),2″-[2H]imidazol]-6′-yl)-5-fluorobenzonitrile

4″-Amino-6′-bromo-5″-methyl-3′H,4H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4-one(Example 115 step 6, 92 mg, 0.26 mmol), 3-cyano-5-fluorophenylboronicacid (42 mg, 0.26 mmol), 3-(di-tert-butylphosphonium)propane sulfonate(6.8 mg, 0.03 mmol), sodium tetrachloropalladate(II) (3.8 mg, 0.01mmol), 2-Me THF (2 mL) and K₂CO₃ (2 M aq., 0.383 mL, 0.77 mmol) wereadded to a microwave vial. The vial was sealed and heated in the MW for30 min at 100° C. EtOAc and water were added and the organic phase wascollected, dried through a phase separator and evaporated to dryness invacuo. The crude product was purified using preparative chromatographyto yield the title compound (39 mg, 38% yield): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.45 (td, 1H), 1.67-1.78 (m, 2H), 1.78-1.90 (m, 1H), 2.08(d, 1H), 2.14-2.23 (m, 4H), 2.34-2.48 (m, 2H), 3.20-3.32 (m, 2H), 6.61(br. s., 2H), 6.94 (s, 1H), 7.45 (d, 1H), 7.63 (d, 1H), 7.74-7.87 (m,2H), 7.93 (s, 1H); MS (MM-ES+APCI)+ m/z 401 [M+H]⁺.

Example 116(1r,4r)-4-Methoxy-5″-methyl-6′-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

An analogous procedure to the procedure described for Example 81 wasfollowed using3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(98 mg, 0.38 mmol) and(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 130 mg, 0.35 mmol). The product waspurified by flash chromatography on silica using gradient elution with0-10% of 0.2 M methanolic ammonia in DCM to give 65 mg (44% yield) ofthe title compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.90-1.01 (m, 1H),1.13-1.33 (m, 2H), 1.46-1.54 (m, 3H), 1.84 (m, 2H), 2.18 (s, 3H), 2.28(s, 3H), 2.91-3.03 (m, 2H), 3.05-3.12 (m, 1H), 3.20 (s, 3H), 6.56 (br.s., 2H), 6.81 (s, 1H), 7.23 (s, 1H), 7.38 (d, 1H), 7.47-7.53 (m, 1H),7.93-7.98 (m, 1H), 8.31 (m, 1H), 11.31 (s, 1H); MS (ES+) m/z 428 [M+H]⁺.

Example 117(1r,4r)-6′-Bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:(1r,40-N-{6′-Bromo-4-[(²H₃)methyloxy]spiro[cyclohexane-1,2′-inden]-1′(3′H)-ylidene}-2-methylpropane-2-sulfinamide

6′-Bromo-4-[(²H₁)methyloxy]spiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 72, 1.66 g, 5.32 mmol), 2-methylpropane-2-sulfinamide(1.20 g, 9.57 mmol) and titanium ethoxide (2.19 mL, 10.6 mmol) weredissolved in 2-Me THF (12 mL) and heated to reflux over the weekend. Themixture was allowed to cool to r.t. whereafter it was diluted with EtOAc(20 mL). Water (15 mL) was added dropwise under vigorous stirring. After10 min the mixture was left standing still without stirring for 1 h. Thesolids were filtered off and the organic layer was concentrated.Purification by flash chromatography using 0-25% EtOAc in heptane aseluent afforded 1.44 g (65% yield) of the title compound as a mixture ofisomers (1r,4r) major and (1s,4s) minor. Major isomer (1r,4r): ¹H NMR(500 MHz, CDCl₃) δ 1.31-1.36 (m, 9H), 1.38 (m, 1H), 1.52-1.68 (m, 4H),1.96-2.07 (m, 1H), 2.13 (dt, 2H), 2.97 (d, 2H), 3.20-3.33 (m, 1H),7.22-7.26 (m, 1H), 7.61 (dd, 1H), 8.46-8.71 (m, 1H). MS (ES+) m/z 415[M+H]⁺.

Step 2:(1r,4r)-6′-Bromo-4-[(²H₃)methyloxy]spiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4 M in 1,4-dioxane, 8.67 mL, 34.7 mmol) was added to a solution ofN-{6′-Bromo-4-[(²H₃)methyloxy]spiro[cyclohexane-1,2′-inden]-1′(3′H)-ylidene}-2-methylpropane-2-sulfinamide(Example 117 step 1, 1.44 g, 3.47 mmol) in anhydrous 1,4-dioxane (5 mL).A white precipitate was formed immediately and the resulting cloudymixture was stirred under an argon atmosphere at r.t. for 45 min. Et₂O(30 mL) was added and the solid was filtered off and washed with Et₂O.The solid was partitioned between DCM and sat. aq. NaHCO₃. The phaseswere separated and the organic layer dried over Na₂SO₄ and concentratedto afford 999 mg (93% yield) of the title compound as a mixture ofisomers (1r,4r) (major) and (1s,4s) (minor) which was used directly inthe next step: MS (ES+) m/z 311 [M+H]⁺.

Step 3:(1r,4r)-6′-Bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

6′-Bromo-4-[(²H₃)methyloxy]spiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 117 step 2, 0.999 g, 3.21 mmol) and trimethyl orthoformate(1.06 mL, 9.63 mmol) in 2-propanol (10 mL) was heated to 80° C.2-Oxopropanethioamide (Intermediate 2, 0.828 g, 8.02 mmol) dissolved in2-propanol (6 mL) was added dropwise over ˜10 min and the resultingorange mixture was stirred at 80° C. under N₂. After 3 h the mixture wasconcentrated to approximately 1/2 the volume and left at 4° C.overnight. The formed solid was filtered off, washed with cold MeOH anddried in vacuo, yielding 0.701 g (55% yield) of the title compound as amixture of isomers (83:27 of (1r,4r) and (1s,4s)). The mother liquor wasconcentrated and the crude product was purified by flash chromatographyusing a gradient of 0-40% EtOAc in heptane to afford another 0.181 g(14% yield) of the title compound as a mixture of isomers (94:6 of(1r,4r) and (1s,4s)). Major isomer (1r,4r): ¹H NMR (500 MHz, DMSO-d₆) δ1.16-1.32 (m, 4H), 1.47 (dd, 2H), 1.81-1.92 (m, 2H), 2.23-2.29 (m, 3H),2.95-3.09 (m, 3H), 6.98 (d, 1H), 7.34 (d, 1H), 7.51 (dd, 1H), 12.35 (s,1H); MS (ES+) m/z 396 [M+H]⁺.

Step 4:(1r,4r)-6′-Bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 117 step 3, 0.701 g, 1.77 mmol) and ammonia (7 M in MeOH, 12mL, 84 mmol) were mixed in a microwave vial. The vial was sealed and thereaction was heated at 100° C. for 30 min in a microwave reactor (fixedhold time). The mixture was concentrated and the residue was dissolvedin new ammonia (7 M in McOH, 12 mL, 84 mmol) and heated again at 100° C.for 30 min in a microwave reactor. This, concentration, addition ofammonia and heating, was repeated once more (3 runs in total). Afterevaporation of the solvent, the residue was partitioned between EtOAcand 2 M citric acid. The phases were separated and the organic layer wasextracted with 2 M citric acid. The organic layer was discarded whilethe combined aqueous phases were basified to pH 12 by addition of 50%NaOH (aq) and extracted with EtOAc ×2. The combined organic layers weretreated with charcoal and filtered through diatomaceous earth. Thefilter pad was rinsed with EtOAc and the organic phase was concentrated,yielding 0.521 g (78% yield) of the title compound as a mixture ofisomers (75:25 of (1r,4r) and (1s,4s)). A pure sample of(1r,4r)-6′-bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-aminewas obtained using a Waters FractionLynx preparative HPLC, with anXBridge C18 (150*19 mm; 5 μm) column, and a mobile phase consisting of5-40% MeCN in 0.1M aq. NH₄OAc over 18 min at a flow rate of 20 mL/minand a temperature at 45° C.: ¹H NMR (500 MHz, DMSO-d₆) δ 0.88-0.98 (m,1H), 1.09-1.26 (m, 2H), 1.35-1.46 (m, 3H), 1.81 (d, 2H), 2.16 (s, 3H),2.86-3.04 (m, 3H), 6.59 (br. s., 2H), 6.65 (s, 1H), 7.25 (d, 1H), 7.34(dd, 1H). MS (ES+) m/z 379 [M+H]⁺.

Example 1183-{(1r,4r)-4″-Amino-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl}-5-fluorobenzonitrile

(1r,4r)-6′-Bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 117, 0.100 g, 0.26 mmol), 3-cyano-5-fluorophenylboronic acid(65 mg, 0.40 mmol), sodium tetrachloropalladate(II) (3.8 mg, 0.01 mmol)and 3-(di-tert-butyl-phosphonium)propane sulfonate (7.1 mg, 0.03 mmol)were put in a microwave vial. 2-Me THF (2 mL) was added followed byK₂CO₃ (2.0 M, 0.395 mL, 0.79 mmol) and the mixture was degassed. Themixture was then heated at 100° C. in a microwave reactor for 30 min.Water and EtOAc were added and the phases were separated. The aqueousphase was extracted with EtOAc and the combined organic layers weredried over MgSO₄ and concentrated. The crude product was purified bypreparative chromatography followed by flash chromatography using agradient of 5% MeOH (containing 0.1M NH₃) in EtOAc to obtain 40 mg (37%yield) of the title compound: ¹H NMR (500 MHz, DMSO-d₆) δ 0.94-1.03 (m,1H), 1.13-1.28 (m, 2H), 1.36-1.50 (m, 3H), 1.82 (d, 2H), 2.18 (s, 3H),2.90-2.98 (m, 1H), 2.98-3.11 (m, 2H), 6.53 (s, 2H), 6.90 (s, 1H), 7.41(d, 1H), 7.59 (dd, 1H), 7.79 (dd, 2H), 7.91 (s, 1H); MS (ES+) m/z 420[M+H]⁺.

Example 119(1r,4r)-6′-(5-Chloropyridin-3-yl)-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (23 mg, 21% yield) was prepared using the proceduredescribed for Example 118 starting from(1r,4r)-6′-bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 117, 0.100 g, 0.26 mmol) and 5-chloropyridin-3-ylboronic acid(0.054 g, 0.34 mmol): ¹H NMR (500 MHz, DMSO-d₆) δ 0.93-1.02 (m, 1H),1.13-1.29 (m, 2H), 1.40-1.50 (m, 3H), 1.80-1.85 (m, 2H), 2.17 (s, 3H),2.91-2.98 (m, 1H), 2.98-3.13 (m, 2H), 6.54 (s, 2H), 6.87 (d, 1H), 7.42(d, 1H), 7.57 (dd, 1H), 8.09 (t, 1H), 8.56 (d, 1H), 8.71 (d, 1H). MS(ES+) m/z 412 [M+H]⁺.

Example 120(1r,4r)-6′-[5-(Difluoromethyl)pyridin-3-yl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 400 mg, 1.06 mmol) was dissolved in 2-MeTHF (3 mL) in a MW-vial.3-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Intermediate 74, 184 mg, 0.72 mmol) was added followed by K₂CO₃ (2.0 Maq.) (1.595 mL, 3.19 mmol). Then sodium tetrachloropalladate(II) (44 mg,0.15 mmol) and 3-(di-tert-butylphosphonium)propane sulfonate (80 mg,0.30 mmol) were added, the system was closed and run in the MW reactorfor 30 min at 100° C. The Water and 2-Me THF were added. The water phasewas eliminated. The organic phase was washed once with brine and water.The organic phase was concentrated in vacuo and the product was purifiedby preparative chromatography to give 7 mg (1.5% yield) of the titlecompound: ¹H NMR (500 MHz, DMSO-d₆) d ppm 0.96 (m, 1H) 1.12-1.31 (m, 2H)1.38-1.55 (m, 3H) 1.83 (d, 2H) 2.17 (s, 3H) 2.91-2.99 (m, 1H) 3.05 (q,2H) 3.20 (s, 3H) 6.56 (br. s, 2H) 6.87 (s, 1H) 7.18 (t, 1H) 7.44 (d, 1H)7.59 (dd, 1H) 8.09 (s, 1H) 8.73 (s, 1H) 8.92 (s, 1H); MS (ES+) m/z 425[M+H]⁺.

Example 121(1r,4r)-4-Methoxy-5″-methyl-6′-(3-methyl-1H-indol-5-yl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 110 mg, 0.29 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (82 mg, 0.32mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (11.9 mg, 0.01 mmol) and potassiumacetate (86 mg, 0.88 mmol) were placed in a microwave vial. 2-Me THF (5mL) was added and the vial was evacuated and refilled with argon. Themixture was heated to 100° C. in a microwave apparatus for 30 min. Tothe resulting mixture was added 5-bromo-3-methyl-1H-indole (74 mg, 0.35mmol), sodium tetrachloropalladate(II) (4.3 mg, 0.01 mmol),3-(di-tert-butylphosphino)propane-1-sulfonic acid (7.8 mg, 0.03 mmol)and 2 M aq. K₂CO₃ (0.438 mL, 0.88 mmol). The vial was evacuated andrefilled with argon. The reaction mixture was heated to 120° C. in amicrowave reactor for 30 min. The reaction mixture was diluted withEtOAc and DCM, washed with water, dried over MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicausing gradient elution with 0-10% (0.2 M ammonia in MeOH) in DCM to give56 mg (44% yield) of the title compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.94 (m, 1H), 1.12-1.32 (m, 2H), 1.49 (m, 3H), 1.84 (m, 2H), 2.17 (s,3H), 2.27 (s, 3H), 2.90-3.01 (m, 2H), 3.03-3.12 (m, 1H), 3.20 (s, 3H),6.55 (s, 2H), 6.77 (s, 1H), 7.11 (s, 1H), 7.20 (m, 1H), 7.30-7.38 (m,2H), 7.46 (m, 1H), 7.54 (s, 1H), 10.75 (s, 1H); MS (ES+) m/z 427 [M+H]⁺.

Example 122(1r,4r)-5″-methyl-4-[(²H₃)methyloxy]-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6-Bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 117, 0.100 g, 0.26 mmol), 5-(prop-1-ynyl)pyridin-3-ylboronicacid (Intermediate 15, 55 mg, 0.34 mmol), sodiumtetrachloropalladate(II) (3.88 mg, 0.01 mmol) and3-(di-tert-butylphosphonium)propane sulfonate (7.07 mg, 0.03 mmol) wereplaced in a microwave vial. 2-Me THF (2 mL) was added followed by aq.K₂CO₃ (2.0 M, 0.395 mL, 0.79 mmol). The mixture was degassed, theatmosphere was exchanged to argon, and the mixture was heated at 100° C.in a microwave reactor for 30 min. The reaction mixture was allowed toreach r.t., and EtOAc and brine were added. The organic phase was driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby preparative chromatography (XBridge C18 (150×19 mm, 5 μm) column anda gradient of 10-40% MeCN in 50 mM aq. NH₄OAc over 18 min at 45° C. witha flow rate of 20 mL/min) to give the title compound (55 mg, 50% yield):¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.90-1.04 (m, 1H), 1.11-1.31 (m, 2H),1.37-1.55 (m, 3H), 1.83 (d, 2H), 2.09 (s, 3H), 2.17 (s, 3H), 2.89-3.14(m, 3H), 6.53 (br. s., 2H), 6.83 (s, 1H), 7.41 (d, 1H), 7.54 (d, 1H),7.90 (s, 1H), 8.51 (s, 1H), 8.67 (d, 1H); MS (ES+) m/z 416 [M+H]⁺.

Example 123(1r,4r)-6′-[2-Chloro-3-(prop-1-yn-1-yl)phenyl]-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

In a microwave vial were(1r,4r)-6′-bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 0.218 g, 0.58 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.162 g,0.64 mmol), 1,1′-bis-(diphenylphosphino)ferrocene-palladium dichloride(24 mg, 0.03 mmol) and potassium acetate (0.114 g, 1.16 mmol) weredissolved in dioxane (7 mL) and was irradiated at 130° C. for 40 min ina microwave reactor. To the mixture was added K₂CO₃ (2 M aq., 0.578 mL,1.16 mmol), tetrakis(triphenylphosphine)palladium (33 mg, 0.03 mmol) anda solution of 1-bromo-2-chloro-3-(prop-1-ynyl)benzene (Intermediate 75,146 mg, 0.64 mmol) in dioxane (2 mL). The vial was sealed and heated at130° C. for 20 min in a microwave reactor. After cooling, the mixturewas diluted with DCM, washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The product was isolated using preparativechromatography to give 25 mg (10% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃) δ ppm 1.15 (td, J=13.40, 2.84 Hz, 1H) 1.30-1.47 (m, 3H)1.67-1.75 (m, 1H) 1.79 (d, J=8.51 Hz, 1H) 1.96-2.10 (m, 2H) 2.12 (s, 3H)2.42 (s, 3H) 3.11 (br. s., 1H) 3.20 (m, 1H) 3.29 (m, 1H) 3.35 (s, 3H)6.87 (s, 1H) 7.18 (q, J=7.99 Hz, 2H) 7.35-7.44 (m, 3H) 8.33 (br. s.,2H); MS (ES+) m/z 446 [M+H]⁺.

Example 1246′-Bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-(5′-Bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

Titanium ethoxide (2.03 mL, 9.85 mmol), 2-methyl-2-propanesulfinamide(0.895 g, 7.39 mmol) and6′-bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 78, 1.71 g, 4.93 mmol) in dry 2-Me THF (30 mL) were heatedto 100° C. to give an azeotrope at 74° C. The azeotropic distillationwas continued for 5 h and then the mixture was refluxed for 2 days. Themixture was cooled to r.t. Water (10 mL) and EtOAc (20 mL) were added,under continuous stirring, while a solid formed. The reaction mixturewas stirred at r.t. for 2 h, and then the formed solid was left tosediment for 1 h. The mixture was filtered, and the solid was washedwith EtOAc. The filtrate was concentrated in vacuo to give a residuethat was purified by flash chromatography (eluent heptane/EtOAc 65/35)to give the title compound (400 mg, 18% yield):

¹H NMR (400 MHz, CDCl₁) δ ppm 1.34-1.37 (m, 9H) 1.56 (s, 4H) 1.73-1.82(m, 2H) 2.13 (br. s., 5H) 2.89 (d, 2H) 7.22 (d, 1H) 7.60 (dd, 1H) 8.53(d, 1H); MS (ES+) 451 [M+H]⁺.

Step 2:6′-Bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

N-(5′-Bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 124 Step 1, 400 mg, 0.89 mmol) was dissolved in dioxane (10mL). The atmosphere was exchanged to argon. Hydrochloric acid (4 M indioxane) (2.22 mL, 8.88 mmol) was added. The reaction mixture wasstirred at 21° C. for 2.5 h. The mixture was concentrated and theresidue was dissolved in DCM (˜4-6 mL). Et₂O (14 mL) was added and thesolid was filtered off and washed with Et₂O. The solid was partitionedbetween DCM (10 mL) and sat. aq. NaHCO₃ (8 mL). The phases wereseparated and the organic layer concentrated in vacuo. The acquiredsolid (340 mg), trimethyl orthoformate (0.292 mL, 2.67 mmol), andN-ethyldiisopropylamine (0.307 mL, 1.78 mmol) in i-PrOH (20 mL) wereheated to 80° C. for 10 min, and then 2-oxopropanethioamide(Intermediate 2, 183 mg, 1.78 mmol) was added. The reaction mixture wasrefluxed for 6 h. The mixture was cooled to r.t., and concentrated invacuo. The residue was diluted with EtOAc, and washed with brine. Theorganic layer was dried over MgSO₄, filtered, and purified by flashchromatography (eluent heptane/EtOAc 80/20) to give the title compound(40 mg, 10% yield): ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37-1.50 (m, 6H)1.66-1.83 (m, 6H) 1.89-2.04 (m, 4H) 2.07-2.22 (m, 2H) 2.44 (s, 4H) 3.00(d, 2H) 7.01 (d, 1H) 7.18 (d, 1H) 7.45 (dd, 1H) 9.04-9.13 (m, 1H); MS(ES+) m/z 433 [M+H]⁺ and (ES−) m/z 431 [M−H]⁻.

Step 3:6′-Bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

6′-Bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 124 Step 2, 40 mg, 0.09 mmol) was dissolved in ammonia (7 M inMeOH) (2 mL, 14.0 mmol) in a microwave vial. The vial was capped, andheated to 110° C. for 30 min in a microwave reactor. The solution wasconcentrated, and the residue dissolved in ammonia (7 M in MeOH) (2 mL,14.0 mmol) and heated to 110° C. in a microwave reactor. This cycle(concentration, addition of ammonia and heating) was repeated until allstarting material was converted to product (6 times). The reactionmixture was cooled to r.t., concentrated in vacuo and purified bypreparative chromatography to give the title compound (8 mg, 21% yield):¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19-1.38 (m, 4H) 1.42-1.59 (m, 3H)1.84-1.92 (m, 1H) 1.98 (m, 1H) 2.20 (s, 3H) 2.76-2.94 (m, 2H) 6.55-6.62(m, 3H) 7.22 (m, 1H) 7.34 (m, 1H); MS (APCI+) 416 [M+H]⁺.

Example 1253-{(1r,4r)-4″-Amino-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl}-5-chlorobenzonitrile

The title compound (40 mg, 35% yield) was prepared using the proceduredescribed for Example 118 starting from(1r,4r)-6′-bromo-5″-methyl-4-[(²H₃)methyloxy]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 117, 0.100 g, 0.26 mmol) and3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 35, 0.114 g, 0.29 mmol): ¹H NMR (500 MHz, DMSO-d₆) δ0.91-1.04 (m, 1H), 1.11-1.30 (m, 2H), 1.35-1.51 (m, 3H), 1.82 (d, 2H),2.18 (s, 3H), 2.90-2.96 (m, 1H), 2.96-3.12 (m, 2H), 6.54 (br. s., 2H),6.89 (s, 1H), 7.41 (d, 1H), 7.58 (dd, 1H), 7.95 (d, 2H), 8.01 (s, 1H).MS (APCI+) m/z 436 [M+H]⁺.

Example 126(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-((1r,4r))-5′-(cyclobutylmethoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 46, 1.48 g, 4.71 mmol) and 2-methylpropane-2-sulfinamide(1.027 g, 8.47 mmol) were dissolved in 2-Me THF (17 mL) and titanium(IV)ethoxide (1.97 mL, 9.41 mmol) was added. The resulting mixture washeated to reflux overnight. 2-Methylpropane-2-sulfinamide (0.560 g, 4.62mmol) was added and the reaction was refluxed for 6 h. Additional2-methylpropane-2-sulfinamide (0.560 g, 4.62 mmol) and titanium(IV)ethoxide (1 mL, 4.79 mmol) were added and the mixture was refluxedovernight. Additional 2-methylpropane-2-sulfinamide (0.560 g, 4.62 mmol)and titanium(IV) ethoxide (1 mL, 4.79 mmol) were added and the mixturewas refluxed overnight by the time the reaction had reached 80%conversion. EtOAc (10 mL) and sat aq. NaHCO₃ (2 mL) were added understirring. The mixture was left to stand still for 1 h. The organic phasewas collected by filtration through diatomaceous earth, dried over MgSO₄and concentrated. The crude product was purified on a silica gel column(gradient elution 0-100% EtOAc in n-heptane) to give the title compound(1.12 g, 57% yield) containing 30% of the (1s,4s)-isomer. It was used assuch in the next step: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.26 (m, 11H),1.50 (m, 3H), 1.87 (m, 5H), 2.06 (m, 4H), 2.73 (m, 1H), 2.96 (m, 2H),3.17 (m, 1H), 3.26 (s, 3H), 3.95 (d, 2H), 7.22 (m, 1H), 7.40 (m, 1H),7.83 (m, 1H); MS (ES+) m/z 418.2 [M+H]⁺.

Step 2:(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4 M in 1,4-dioxane) (6.70 mL, 26.8 mmol) was added to a solution ofN-((1r,4r)-5′-(cyclobutylmethoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 126 Step 1, 1.12 g, 2.68 mmol) in anhydrous 1,4-dioxane (8 mL).The reaction mixture was stirred under a nitrogen atmosphere at r.t. for90 min. DCM (20 mL) and sat aq. NaHCO₃ (15 mL) were added to thereaction mixture. The phases were separated and the organic layerconcentrated to give the title compound (0.840 g, quantitative yield),that was used directly in next step: MS (ES+) m/z 314.15 [M+H]^(|).

Step 3:(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 126 Step 2, 0.84 g, 2.68 mmol) and 2-oxopropanethioamide(Intermediate 2, 0.829 g, 8.04 mmol) were dissolved in dry MeOH (12 mL)and the resulting orange solution was heated at 60° C. under N₂ (g)overnight. Additional 2-oxopropanethioamide (Intermediate 2, 0.829 g,8.04 mmol) was added to the reaction mixture and it was heated to 60° C.for 6 h, but there was no desired product in the mixture. The reactionmixture was concentrated and the solvent was changed to 2-propanol (12mL) and trimethyl orthoformate (0.880 mL, 8.04 mmol) was added. Thereaction mixture was heated to 80° C. for approximately 2 days (20%conversion). The mixture was concentrated. The residue was dissolved inEtOAc and then washed with water. The organic phase was concentrated andthe residue was purified on a silica gel column (0-100% EtOAc inn-heptane) to give the title compound (0.140 g, 13% yield). The productcontained 15% of the (1s,4s)-isomer and was used as such in the nextstep: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.09 (m, 1H) 1.24 (m, 3H) 1.49 (m,2H) 1.85 (m, 6H) 2.03 (m, 2H) 2.26 (s, 3H) 2.64 (dt, 1H) 2.97 (m, 3H)3.20 (s, 3H) 3.85 (m, 2H) 6.30 (d, 1H) 6.87 (dd, 1H) 7.23 (d, 1H) 12.29(s, 1H); MS (ES+) m/z 399.1 [M+H]⁺.

Step 4:(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-(Cyclobutylmethoxy)-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 126 Step 3, 140 mg, 0.35 mmol) and ammonia (7 M in MeOH) (1.5mL, 10.5 mmol) was microwaved for 40 min. at 100° C. The mixture wasconcentrated and then re-dissolved in ammonia (7 M in MeOH) (1.5 mL,10.5 mmol). The mixture was microwaved for 40 min. at 110° C. Thisprocedure (concentration, dissolution in ammonia and heating) wasrepeated 4 times. The crude product was purified on a silica gel column(4 g SiO₂, gradient elution of 0-100% (7 M NH₃ in MeOH/DCM 1:9) in DCM)followed by preparative chromatography to give the title compound (44.0mg, 28% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.90 (t, 1H) 1.17 (m,2H) 1.41 (m, 3H) 1.82 (m, 9H) 2.01 (m, 2H) 2.14 (s, 3H) 2.62 (m, 1H)2.90 (m, 3H) 3.18 (s, 3H) 3.78 (m, 2H) 6.05 (s, 1H) 6.46 (br. s, 2H)6.70 (d, 1H) 7.14 (d, 1H); MS (APCI+) m/z 382.2 [M+H]⁺.

Example 1275-[(1r,4r)-4″-Amino-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-2-fluoro-3-(methoxymethyl)benzonitrile

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 19 Method B Step 4, 328 mg, 0.87 mmol) was dissolved in 2-MeTHF (5 mL).2-Fluoro-3-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 86, 254 mg, 0.87 mmol) was added to the above solutionfollowed by K₂CO₃ (2.0 M aq.) (1.3 mL, 2.61 mmol). Sodiumtetrachloropalladate(II) (35.9 mg, 0.12 mmol) and3-(di-tert-butylphosphonium)propane sulfonate (65.5 mg, 0.24 mmol) wereadded, the MW-vial was closed and heated in the microwave reactor for 30min at 100° C. The mixture was transferred to a separation funnel, andwater and 2-Me THF was added. The water phase was eliminated. Theorganic phase was washed once with brine and water. The organic phasewas concentrated in vacuo and the product was purified by preparativechromatography to give (23 mg, 5% yield) of the title compound: ¹H NMR(500 MHz, CDCl₃) δ ppm 1.12 (td, 1H), 1.31-1.45 (m, 2H), 1.45-1.56 (m,1H), 1.71 (t, 2H), 1.98 (d, 2H), 2.36 (s, 3H), 3.04-3.15 (m, 1H), 3.22(q, 2H), 3.35 (s, 3H), 3.45 (s, 3H), 4.56 (s, 2H), 6.89 (s, 1H),7.36-7.45 (m, 2H), 7.65 (d, 1H), 7.81 (d, 1H); (ES+) m/z 461 [M+H]⁺.

Example 1286′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-(5′-Bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide

Titanium ethoxide (0.893 mL, 4.33 mmol), 2-methylpropane-2-sulfinamide(0.315 g, 2.60 mmol) and6′-bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one(Intermediate 91, 0.713 g, 2.17 mmol) were dissolved in 2-Me THF (5 mL)and heated to 90° C. overnight. 2-Methylpropane-2-sulfinamide (0.315 g,2.60 mmol) and titanium ethoxide (0.893 mL, 4.33 mmol) were added andthe reaction was refluxed for 7 h. Another portion of reagents was addedand the mixture was refluxed overnight. The reaction was allowed toattain r.t. EtOAc (50 mL) was added followed by dropwise addition ofNaHCO₃ (10 mL). The mixture was stirred at r.t. for 2 h. The crudeproduct was purified using flash chromatography (40 g SiO₂, 0-40% EtOAcin heptane) to give the title compound (564 mg, 60% yield): MS (ES+) m/z432 [M+H]⁺.

Step 2:6′-Bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4 M in 1,4-dioxane) (3.26 mL, 13.0 mmol) was added to a suspensionofN-(5′-bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 128 Step 1, 0.564 g, 1.30 mmol) in 1,4-dioxane (5 mL) and theresulting mixture was stirred under a nitrogen atmosphere at r.t.overnight. The formed precipitate was filtered off and washed with Et₂O.The solid was then dissolved in DCM and sat. aq. NaHCO₃. The mixture waspoured into a phase separator, the organic layer was collected andconcentrated to yield the title compound that was used as such in thenext step: MS (CI) m/z 328 [M+H]⁺.

Step 3:6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

6′-Bromo-4-(difluoromethyl)spiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 128 Step 2, 0.310 g, 0.94 mmol), trimethyl orthoformate (0.209mL, 1.89 mmol) and 2-propanol (4 mL) was heated to 80° C.2-Oxopropanethioamide (Intermediate 2, 0.244 g, 2.36 mmol) in 2-propanol(1 mL) was added and the mixture was heated for 3.5 h. The mixture wasconcentrated and then MeOH was added. The reaction was left standing ina refrigerator over a weekend. The solvent was evaporated and the crudeproduct was purified using flash chromatography (40 g SiO₂, 0-100% EtOAcin heptane) to give the title compound (300 mg, 77% yield): MS (ES+) m/z413 [M+H]⁺.

Step 4:6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 128 Step 3, 0.3 g, 0.73 mmol) was taken up in ammonia (7 M inMeOH) (6.22 mL, 43.6 mmol) and the resulting mixture was heated in themicrowave reactor at 110° C. for 30 min. The solvent was evaporated. Thesame amount of ammonia was added and the mixture was heated andconcentrated (5 times). The crude material was dissolved in EtOAc. Aq.citric acid solution (0.1 M) was added and the phases were separated.The citric acid phase was basified with 1 M NaOH and extracted with DCMtwice. The combined DCM extracts were concentrated to give the titlecompound (0.120 g, 42% yield). 20 mg of the product was purified bypreparative chromatography to give 11 mg of the title compound: ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.19-1.31 (m, 3H), 1.34-1.48 (m, 3H), 1.66-1.82(m, 2H), 1.90 (d, 1H), 2.20 (s, 3H), 2.80-2.95 (m, 2H), 5.53-5.97 (m,1H), 6.53 (s, 2H), 6.59 (s, 1H), 7.21 (d, 1H), 7.33 (d, 1H); MS (ES+)m/z 396 [M+H]⁺.

Example 1296′-(5-Chloropyridin-3-yl)-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 128, 0.1 g, 0.25 mmol), 5-chloropyridin-3-yl boronic acid(0.048 g, 0.30 mmol), 3-(di-tert-butylphosphonium)propane sulfonate(6.77 mg, 0.03 mmol), sodium tetrachloro-palladate(II) (3.71 mg, 0.01mmol), 2-Me THF (2 mL) and aq. K₂CO₃ (2.0 M, 0.379 mL, 0.76 mmol) wereadded to a microwave vial. The vial was sealed and evacuated andrefilled with Ar (g) and then heated in the microwave reactor for 30 minat 100° C. The same amount of Pd-catalyst, ligand and boronic ester wereadded and the vial was sealed and evacuated and refilled with Ar (g).The vial was heated in the microwave reactor for 30 min at 100° C. EtOAcand water were added and the organic phase was extracted, dried througha phase separator and evaporated to dryness. The crude product waspurified using preparative chromatography to give the title compound (12mg, 11% yield): ¹H NMR (500 MHz, CD₃CN) δ ppm 1.24-1.41 (m, 4H),1.45-1.54 (m, 3H), 1.71-1.86 (m, 1H), 2.00 (dt, 1H), 2.24 (s, 3H), 2.98(d, 1H), 3.07 (d, 1H), 5.32 (br. s., 2H), 5.64 (d, 1H), 6.86 (d, 1H),7.38 (d, 1H), 7.50 (dd, 1H), 7.93 (t, 1H), 8.49 (d, 1H), 8.65 (d, 1H);MS (MM-ES+APCI)+ m/z 429 [M+H]⁺.

Example 130(1r,4r)-6′-Bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amineStep 1:N-[(1r,1′E,4r)-6′-Bromo-4-ethoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-ylidene]-2-methylpropane-2-sulfinamide

6′-Bromo-4-ethoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate80, 3.7 g, 11.4 mmol, as a 2:1 mixture of isomers),2-methylpropane-2-sulfinamide (2.77 g, 22.9 mmol) and titanium ethoxide(8.26 mL, 40.1 mmol) were dissolved in 2-Me THF (30 mL) and heated toreflux for 48 h. The reaction was left to cool down. EtOAc (100 mL) andNaHCO₃ (aq. Sat, 30 mL) were added under stiffing. The mixture wasallowed to stand still for 1 h. The organic phase was collected byfiltration, dried over MgSO₄ and concentrated. Flash chromatography(twice) using 0-20% EtOAc in n-heptane gave the title compound (1.48 g,30% yield): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (t, 3H) 1.24 (s, 9H)1.30 (m, 2H) 1.44-1.57 (m, 2H) 1.66 (br. s, 2H) 1.99 (d, 2H) 3.01 (s,2H) 3.23-3.32 (m, 1H) 3.48 (q, 2H) 7.48 (d, 1H) 7.78 (d, 1H) 8.53 (br.s, 1H); MS (ES+) m/z 426 [M+H]⁺.

Step 2:(1r,4r)-6′-Bromo-4-ethoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine

HCl (4 M in 1,4-dioxane) (12.7 mL, 50.9 mmol) was added to a solution ofN-((1r,4r)-5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide(Example 130 Step 1, 2.17 g, 5.09 mmol) in anhydrous 1,4-dioxane (25 mL)and the resulting mixture was stirred under a nitrogen atmosphere at rtfor 90 min. A white precipitate formed. Et₂O (30 mL) was added and thesolid was filtered off and washed with Et₂O (10 mL). The solid waspartitioned between DCM (20 mL) and sat. aq. NaHCO₃ (20 mL). The phaseswere separated and the organic layer dried over Na₂SO₄ and concentrated.The crude product (1.2 g, 73% yield) was used directly in the next step:MS (EI) m/z 322 M^(|).

Step 3:(1r,4r)-6′-Bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione

(1r,4r)-6′-Bromo-4-ethoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine(Example 130 Step 2, 1.2 g, 3.72 mmol) and 2-oxobutanethioamide(Intermediate 2, 1.15 g, 11.2 mmol) were dissolved in MeOH (80 mL) andwas heated at 60° C. overnight. The reaction was concentrated and theobtained product was used as such in the next step: MS (ES+) m/z 407[M+H]⁺.

Step 4:(1r,4r)-6′-Bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione(Example 130 Step 3) was dissolved in ammonia (7 M in MeOH) (18 mL, 126mmol) and placed in a microwave vial. The vial was sealed and thereaction was heated at 120° C. for 30 min in a microwave reactor. Themixture was concentrated and the residue was dissolved in ammonia (7 Min MeOH) (18 mL, 126 mmol) and heated once more at 120° C. for 30 min ina microwave reactor. This procedure (concentration, addition of ammoniaand heating) was repeated 3 more times. After evaporation of the solventwas the residue subjected to flash chromatography using 0-7% of MeOH(containing NH₃) in DCM as eluent followed by purification bypreparative chromatography to give the title compound (600 mg, 41% yieldover two steps): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87-0.98 (m, 1H), 1.06(t, 3H), 1.11-1.32 (m, 2H), 1.35-1.48 (m, 3H), 1.78 (dt, 2H), 2.16 (s,3H), 2.90 (d, 1H), 2.97-3.08 (m, 2H), 3.39 (q, 2H), 6.58 (br. s, 2H),6.64 (d, 1H), 7.25 (d, 1H), 7.34 (dd, 1H); MS (ES+) m/z 390 [M+H]⁺.

Example 131(1r,4r)-4-ethoxy-5″-methyl-6′-[5-(trifluoromethyl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

(1r,4r)-6′-Bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 130, 100 mg, 0.26 mmol) was dissolved in 2-Mc THF (5 mL) and5-(trifluoro-methyl)pyridin-3-ylboronic acid (73.4 mg, 0.38 mmol) wasadded to the above solution followed by K₂CO₃ (2.0M aq, 0.384 mL, 0.77mmol). Then, sodium tetrachloropalladate(II) (10.5 mg, 0.04 mmol) and3-(di-tert-butylphosphonium)propane sulfonate (19 mg, 0.07 mmol) wereadded, the system closed (MW vial) and run in the microwave reactor for30 min at 100° C. The reaction mixture was cooled to r.t., diluted withEtOAc, and washed with brine. The organic layer was collected, driedover MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by preparative chromatography, providing 25 mg (21% yield) ofthe title compound: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (td, 1H), 1.07(t, 3H), 1.14-1.34 (m, 2H), 1.37-1.51 (m, 3H), 1.81 (dt, 2H), 2.17 (s,3H), 2.96-3.18 (m, 3H), 3.41 (q, 2H), 6.55 (br. s, 2H), 6.93 (d, 1H),7.45 (d, 1H), 7.63 (dd, 1H), 8.28 (s, 1H), 8.91 (s, 1H), 9.05 (d, 1H);MS (ES+) m/z 457 [M+H]⁺.

Example 1323-[(1r,4r)-4″-amino-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-fluorobenzonitrile

The title compound (9 mg, 9% yield) was prepared using the methoddescribed in Example 131 starting from(1r,4r)-6′-Bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 130, 0.86 mg, 0.22 mmol) and 3-cyano-5-fluorophenylboronic acid(44 mg, 0.26 mmol): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.91 (m, 1H), 1.00(t, 3H), 1.06-1.27 (m, 2H), 1.27-1.43 (m, 3H), 1.67-1.82 (m, 2H), 2.11(s, 3H), 2.88-3.07 (m, 3H), 3.34 (q, 2H), 6.46 (s, 2H), 6.83 (s, 1H),7.34 (d, 1H), 7.52 (dd, 1H), 7.65-7.80 (m, 2H), 7.84 (s, 1H); MS (ES+)m/z 431 [M+H]⁺.

Example 133(1r,4r)-6′-(5-chloropyridin-3-yl)-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (34 mg, 36% yield) was prepared using the methoddescribed in Example 26a starting from(1r,4r)-6′-bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 130, 88 mg, 0.23 mmol) and 5-chloropyridin-3-ylboronic acid(53.2 mg, 0.34 mmol), with the exception that the reaction time was 30min and that the product was purified by preparative chromatography: ¹HNMR (500 MHz, DMSO-d₆) δ ppm 0.97 (td, 1H), 1.06 (t, 3H), 1.13-1.32 (m,2H), 1.35-1.49 (m, 3H), 1.74-1.86 (m, 2H), 2.17 (s, 3H), 2.96-3.14 (m,3H), 3.40 (q, 2H), 6.53 (br. s, 2H), 6.87 (d, 1H), 7.42 (d, 1H), 7.57(dd, 1H), 8.08 (t, 1H), 8.56 (d, 1H), 8.70 (d, 1H); MS (ES+) m/z 423[M+H]⁺.

Example 1343-[(1r,4r)-4″-Amino-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-6′-yl]-5-(difluoromethyl)benzonitrile

The title compound (50 mg, 48% yield) was prepared using the methoddescribed in Example 26a starting from(1r,4r)-6′-bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 130, 88 mg, 0.23 mmol) and3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Intermediate 56, 88 mg, 0.23 mmol), with the exception that thereaction was heated for 30 min and that the product was purified bypreparative chromatography: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (m,1H), 1.07 (t, 3H), 1.14-1.33 (m, 2H), 1.40-1.50 (m, 3H), 1.80 (m, 2H),2.17 (s, 3H), 2.96-3.14 (m, 3H), 3.41 (q, 2H), 6.55 (br. s, 2H), 6.90(s, 1H), 7.13 (t, 1H), 7.43 (d, 1H), 7.60 (dd, 1H), 8.01 (d, 2H), 8.22(s, 1H); MS (ES+) m/z 463 [M+H]⁺.

Example 135(1r,4r)-4-Ethoxy-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine

The title compound (50 mg, 40% yield) was prepared as described forExample 26a starting from(1r,4r)-6-bromo-4-ethoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine(Example 130, 113 mg, 0.29 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronicacid (Intermediate 15, 56 mg, 0.35 mmol), with the exception that thereaction was heated for 30 min and the product purified by preparativechromatography: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.97 (td, 1H), 1.06 (t,3H), 1.13-1.33 (m, 2H), 1.35-1.51 (m, 3H), 1.80 (dd, 2H), 2.09 (s, 3H),2.17 (s, 3H), 2.94-3.13 (m, 3H), 3.41 (q, 2H), 6.53 (br. s., 2H), 6.83(s, 1H), 7.40 (d, 1H), 7.54 (dd, 1H), 7.90 (s, 1H), 8.51 (d, 1H), 8.67(d, 1H); MS (ES+) m/z 427 [M+H]⁺.

Biological Assays

The level of activity of the compounds was tested using the followingmethods:

TR-FRET Assay

The β-secretase enzyme used in the TR-FRET is prepared as follows:

The cDNA for the soluble part of the human β-Secretase (AA 1-AA 460) wascloned using the ASP2-Fc10-1-IRES-GFP-neoK mammalian expression vector.The gene was fused to the Fc domain of IgG1 (affinity tag) and stablycloned into HEK 293 cells. Purified sBACE-Fc was stored in −80° C. inTris buffer, pH 9.2 and had a purity of 40%.

The enzyme (truncated form) was diluted to 6 μg/mL (stock 1.3 mg/mL) andthe substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM (stock 120 μM) inreaction buffer (NaAcetate, chaps, triton x-100, EDTA pH4.5). Therobotic systems Biomek FX and Velocity 11 were used for all liquidhandling and the enzyme and substrate solutions were kept on ice untilthey were placed in the robotic system. Enzyme (9 μl) was added to theplate then 1 μl of compound in dimethylsulphoxide was added, mixed andpre-incubated for 10 minutes. Substrate (10 μl) was then added, mixedand the reaction proceeded for 15 minutes at r.t. The reaction wasstopped with the addition of Stop solution (7 μl, NaAcetate, pH 9). Thefluorescence of the product was measured on a Victor II plate readerwith an excitation wavelength of 340 nm and an emission wavelength of615 nm. The assay was performed in a Costar 384 well round bottom, lowvolume, non-binding surface plate (Corning #3676). The finalconcentration of the enzyme was 2.7 μg/ml; the final concentration ofsubstrate was 100 nM (Km of ˜250 nM). The dimethylsulphoxide control,instead of test compound, defined the 100% activity level and 0%activity was defined by wells lacking enzyme (replaced with reactionbuffer). A control inhibitor was also used in dose response assays andhad an 1050 of ˜150 nM.

Diluted TR-FRET Assay

Compounds with a high affinity were further tested in a diluted TR-FRETassay, conditions as described above for the TR-FRET assay, but with 50times less enzyme and a 6.5 h long reaction time at r.t. in the dark.

sAPPβ Release Assay

SH-SY5Y cells were cultured in DMEM/F-12 with Glutamax, 10% FCS and 1%non-essential amino acids and cryopreserved and stored at −140° C. at aconcentration of 7.5-9.5×10⁶ cells per vial. Thaw cells and seed at aconc. of around 10000 cells/well in DMEM/F-12 with Glutamax, 10% FCS and1% non-essential amino acids to a 384-well tissue culture treated plate,100 μL cell susp/well. The cell plates were then incubated for 7-24 h at37° C., 5% CO₂. The cell medium was removed, followed by addition of 30μL compound diluted in DMEM/F-12 with Glutamax, 10% FCS, 1%non-essential amino acids and 1% PeSt to a final conc. of 1% DMSO. Thecompounds were incubated with the cells for 17 h (overnight) at 37° C.,5% CO₂. Meso Scale Discovery (MSD) plates were used for the detection ofsAPPIβ release. MSD sAPPIβ plates were blocked in 1% BSA in Tris washbuffer (40 μL/well) for 1 h on shake at r.t. and washed 1 time in Triswash buffer (40 μL/well). 20 μL of medium was transferred to thepre-blocked and washed MSD sAPPIβ microplates, and the cell plates werefurther used in an ATP assay to measure cytotoxicity. The MSD plateswere incubated with shaking at r.t. for 2 h and the media discarded. 10μL detection antibody was added (1 nM) per well followed by incubationwith shaking at r.t. for 2 h and then discarded. 40 μL Read Buffer wasadded per well and the plates were read in a SECTOR Imager.

ATP Assay

As indicated in the sAPPIβ release assay, after transferring 20 μLmedium from the cell plates for SAPPβ detection, the plates were used toanalyse cytotoxicity using the ViaLight™ Plus cellproliferation/cytotoxicity kit from Cambrex BioScience that measurestotal cellular ATP. The assay was performed according to themanufacture's protocol. Briefly, 10 μL cell lysis reagent was added perwell. The plates were incubated at r.t. for 10 min. Two min afteraddition of 25 μL reconstituted ViaLight™ Plus ATP reagent, theluminescence was measured in a Wallac Victor2 1420 multilabel counter.Tox threshold is a signal below 75% of the control.

Results

Typical IC₅₀ values for the compounds of the present invention are inthe range of about 0.1 to about 100,000 nM. Biological data onexemplified final compounds is given below in Table 2.

TABLE 2 IC₅₀ in IC₅₀ in TR-FRET IC₅₀ in sAPPβ TR-FRET IC₅₀ in sAPPβassay release assay assay release assay Example (nM) (nM) Example (nM)(nM)  1  157 587  2  743 941  3  1700 2880  4  3200 —  5  3640 —  6 4250 —  7  6710 —  8 16300 —  9  1680 2450  10  6850 —  11  1980 —  12 1800 —  13a  1300 501  13c  1890 463  13d  112 239  13e   22^(a) 106 13f  6460 —  13i  560 160  15  112 46  19 Isomer 1   53^(a) 18  19Isomer 2 10300  19 Isomer 3  3330  19 Isomer 4 16600  20a   2.2^(a) 0.28 20a Isomer 1   0.57^(a) 0.10  20a Isomer 2  7720 —  20b   2.3^(a) 0.78 20c   5.2^(a) 1.7  20d   1.6^(a) 0.72  20d Isomer 1   0.63^(a) 0.26 20e   2.3^(a) 0.67  20e Isomer 1   1.1^(a) 0.57  20f   5.5^(a) 3.3  20g  7.1^(a) 2.6  20h   15^(a) 7.1  20g Isomer 1   2.5^(a) 1.8  20h Isomer1  1910 277  20h Isomer 2   21 5.0  20i   4.8^(a) 4.6  20i Isomer 114500  20i Isomer 2   2.2^(a) 2.3  20j   47 91  20k   34^(a) 8.6  20n  17^(a) 3.7  20o   28^(a) 9.2  20q   20^(a) 3.8  20t   20 0.56  20tIsomer 1   0.89^(a) 0.36  20t Isomer 2  8360 —  20u   22 0.63  20v   251.2  20w   18^(a) 5.7  20x  121 29  20y   4.9^(a) 1.2  20z   1.4^(a) 5.2 20aa   1.6^(a) 0.72  25  7530 —  26a  100 53  26c  145 140  27  1760399  28c   53 109  28d  408 89  28h   7.3^(a) 18  29  674 848  30b  5.3^(a) 284  30d   5.2^(a) 97  30c   1.4^(a) 2.2  46a Isomer 1  124419  46a Isomer 2   91 125  46b Isomer 1  180 426  46b Isomer 2  147 185 47 Isomer 1 inactive —  47 Isomer 2  1030 657  47 Isomer 3 inactive — 47 Isomer 4 65300 —  47 Isomer 5 19800 —  47 Isomer 6  1380 —  47Isomer 7 inactive —  47 Isomer 8  8100 —  48 Isomer 1   0.7^(a) 20  48Isomer 2  2030 —  48 Isomer 3  7040  48 Isomer 4  803 689  48 Isomer 535700 —  48 Isomer 6  2570 —  48 Isomer 7   10^(a) 191  48 Isomer 8  14^(a) 204 49 Isomeric   10.000 — mixture 1 49 Isomeric inactive — 50Isomeric  100 597 mixture 2 mixture 1 50 Isomeric   5^(a) 17  51 75600 —mixture 2  52  325 91  53   62 21  54  6610 —  55  284 118  56   31 24 57 Isomer 1   19^(a) 19  57 Isomer 2 27600 —  58  523 219  59  2610 — 60   12^(a) 8.7  61   5.9^(a) 3.1  62   19^(a) 8.6  63   89 29  64  401125  65   5.7^(a) 3.4  66 Isomer 1   2.9^(a) 1.6  66 Isomer 2 16300 — 67   2.0^(a) 0.81  68 Isomer 1   1.2^(a) 0.38  68 Isomer 2  9970 —  69  21^(a) 10  70   18^(a) 13  71 Isomer 1   7.4^(a) 5.2  71 Isomer 2 6720 763  72   2.3^(a) 0.76  73   1.3^(a) 1.0  74   2.6^(a) 2.1  75  5.7^(a) 2.1  76 Isomer 1   3.4^(a) 1.2  76 Isomer 2  636 —  77 16300 — 78  101^(a) 56  79  188 171  80   22^(a) 13  81   23 20  82   66 36  83  21 2.9  84   2.1^(a) 0.99  85   3.1^(a) 0.80  86   1.5^(a) 1.1  87  2.2^(a) 0.93  88   2.8^(a) 4.8  89   3.3^(a) 1.7  90   13^(a) 14  91  2.2a 0.62  92 Isomer 1   0.84^(a) 0.27  92 Isomer 2  5870 —  93  1.8^(a) 0.56  94 Isomer 1   0.7^(a) 0.17  94 Isomer 2  4950 —  95  5.3^(a) 3.6  96   6.1^(a) 3.5  97 Isomer 1   3.1^(a) 1.4  97 Isomer 215400 —  98   1.5^(a) 0.82  99   3.9^(a) 5.7 100   0.72^(a) 0.59 101  19.8 6.3 102   3.3^(a) 2.5 103   34 14 104   64 34 105   22 9.7 106  1.0^(a) 1.1 107   21 7.9 108   1.3^(a) 1.8 109   21 28 110   24 4.0111   51 31 112   22 2.0 113   24 1.6 114   1.2^(a) 0.14 115  632 293116   26 12 117  163 47 118   23 2.8 119   23 0.97 120   27 3.1 121   3710 122   25 0.30 123  189 135 124 19300 6950 125   20 0.50 126   20 1.4127   34 5.1 128  2610 — 129  748 417 130  842 148 131   44 24 132   2117 133   25 5.5 134   28 7.7 135   22 0.85 ^(a)IC₅₀ from the dilutedFRET assay.X-Ray Crystal Structure Determination of Example CompoundsCocrystallized with the BACE1 Protein

Protein Expression, Purification and Crystallization

Human BACE, CID1328 14-453, was cloned, expressed, refolded, activatedand purified according to previously published protocols (Patel, S.,Vuillard, L., Cleasby, A., Murray, C. W., Yon, J. J Mol Biol 2004, 343,407). The protein buffer was exchanged to 20 mM Tris pH 8.5, 150 mM NaCland concentrated to 3.5 mg/mL. Concentrated protein was mixed 1:1 with astock of 11% PEG6k, 100 mM Na acetate pH 5.0 at RT and crystallizedusing vapor diffusion techniques in combination with seeding. Thecrystals were soaked with 10 mM of an example compound, 10% DMSO, 18%PEG6000, 90 mM Na acetate pH 4.85, 18 mM Tris pH 8.5 and 135 mM NaCl for24 hours and flash frozen in liquid nitrogen using 20% glycerol as acryoprotectant.

Data Collection and Refinement

X-ray diffraction data of Example 48 Isomer 1, Example 48 Isomer 7 orExample 48 Isomer 8 soaked crystals were collected at the EuropeanSynchrotron Radiation Facility beamlines ID23-1 and ID29, GrenobleFrance, to resolutions between 1.35-1.45 Å. Data of the compound ofExample 20d Isomer 1 was collected on a Rigaku FR-E+ SuperBrightrotating anode and a HTC imaging plate to a resolution of 1.80 Å. Alldata were indexed and integrated with MOSFLM (Leslie, A. G. W. JointCCP4+ESF-EAMCB Newsletter on Protein Crystallography 1992, 26, 27) andscaled with SCALA (Collaborative Computational Project 4, 1994) in spacegroup P212121, with cell dimensions of about [48,76,105], giving aMatthews coefficient of 2.2 Å³/Da with one monomer per asymmetric unit.The structures of Example 48 Isomer 1, Example 48 Isomer 7 and Example48 Isomer 8 were determined by rigid body refinement of a previouslydetermined BACE-1 structure based on the published 1FKN structure (Hong,L., Koelsch, G., Lin, X., Wu, S., Terzyan, S., Ghosh, A. K., Zhang, X.C., Tang, J. Science 2000, 290, 5489, 150-153) using Refmac5 (Murshudov,G. N., Vagin, A. A., Dodson, E. J. Acta Crystallogr., Sect. D 1997, 53,240). The initial models were further refined by alternative cycles ofmodel rebuilding in Coot (Emsley, P., Cowtan, K. Acta Crystallogr.,Sect. D 2004, 60, 2126) and refinement in Refmac5 and AutoBuster(Bricogne, G., Blane, E., Brandl, M., Flensburg, C., Keller, P.,Paciorek, W., Roversi, P., Sharff, A., Smart, O., Vonrhein, C., Womack,T. Global Phasing Ltd, Cambridge, UK 2010). Strong 5-15 sigma Fo-Fcdensity in the vicinity of the BACE active site indicated the locationof the bound compound. Restraints for the isomers of Example 48 weregenerated by Writedict (Wlodek S., Skillman A. G., Nicholls A., ActaCrystallogr., Sect. D 2006, 62, 741-749) and used by Flynn (Wlodek S.,Skillman A. G., Nicholls A., Acta Crystallogr., Sect. D 2006, 62,741-749) to determine the absolute configuration of the compound ofinterest based on the refined omit maps. Final refinement of theBACE-inhibitor complexes was performed in Refmac5 and AutoBuster.Resulting 2Fo-Fc maps of Example 20d Isomer 1, Example 48 Isomer 1,Example 48 Isomer 7 and Example 48 Isomer 8 can be seen in FIGS. 1-4.Full data collection and refinement statistics can be found in Table 3.

TABLE 3 Data collection and refinement statistics Example 20d Example 48Example 48 Example 48 Isomer 1 Isomer 1 Isomer 8 Isomer 7 Datacollection Space group P2₁2₁2₁ P2₁2₁2₁ P2₁2₁2₁ P2₁2₁2₁ Cell dimensions(Å) 47.8, 76.7, 47.9, 76.2, 47.9, 75.9, 48.6, 74, 104.8 104.7 104.5104.6 Resolution (Å) 1.80-35.58 1.40-38.1 1.45-34.82 1.35-34.92R_(merge) 0.047 (0.452) 0.057 (0.769) 0.107 (1.502) 0.088 (1.128) <I/σI>14.1 (2.3)  11.7 (1.2)  8.6 (1.2) 7.1 (1.0) Completeness (%) 93.6 (83.4)98.8 (89.5) 100 (100) 98.9 (96.5) Redundancy 3.8 (3.9) 3.7 (2.7) 4.6(4.5) 3.7 (3.2) Refinement Resolution (Å) 1.80-30.0 1.40-30.0 1.45-30.01.35-25.0 Measured reflections 129173 281786 318526 303172 Uniquereflections 33553 75301 68326 82658 R_(work)/R_(free) 0.193/0.2350.189/0.216 0.200/0.231 0.192/0.218 No. atoms Protein 3014 3064 29783017 Water 183 310 318 313 Ligand 31 29 29 29 Average B-factors Protein(Å²) 29.6 18.9 18.5 16.3 Water (Å²) 35.1 29.2 28.5 26.6 Ligand (Å²) 22.716.0 16.1 16.4 Ramachandran outliers 0.97 1.69 1.64 0.96 (%) R.m.sdeviations Bond lengths (Å) 0.012 0.015 0.016 0.016 Bond angles (°) 1.581.62 1.66 1.69 ¹Values in parentheses refer to highest-resolution shell.

1-25. (canceled)
 26. A compound which is(1r,1′R,4R)-4″-amino-5″-methyl-6′-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3′H-dispiro[cyclohexane-1,2′-indene-1,2″-imidazol]-4-ol

or a pharmaceutically acceptable salt thereof.
 27. A pharmaceuticalcomposition comprising: a therapeutically effective amount of a compoundor a pharmaceutically acceptable salt thereof according to claim 26; andat least one pharmaceutically acceptable excipient, carrier r diluent.28. A method of treating Alzheimer's Disease in a patient in needthereof, wherein the method comprises administering to said patient atherapeutically effective amount of a compound or a pharmaceuticallyacceptable salt thereof according to claim
 26. 29. A method of treatingAlzheimer's Disease in a patient in need thereof, wherein the methodcomprises administering to said patient a therapeutically effectiveamount of a pharmaceutical composition according to claim 27.